Methods and compositions for the specific inhibition of alpha-1 antitrypsin by double-stranded rna

ABSTRACT

This invention relates to compounds, compositions, and methods useful for reducing α-1 antitrypsin target RNA and protein levels via use of dsRNAs, e.g., Dicer substrate siRNA (DsiRNA) agents.

RELATED APPLICATIONS

The present application claims priority to, and the benefit under 35U.S.C. § 119(e) of the following applications: U.S. provisional patentapplication No. 61/842,551, entitled “Methods and Compositions for theSpecific Inhibition of Alpha-1 Antitrypsin by Double-Stranded RNA,”filed Jul. 3, 2013; and U.S. provisional patent application No.61/891,548, entitled “Methods and Compositions for the SpecificInhibition of Alpha-1 Antitrypsin by Double-Stranded RNA,” filed Oct.16, 2013. The entire contents of the aforementioned patent applicationsare incorporated herein by this reference.

FIELD OF THE INVENTION

The present invention relates to compounds, compositions, and methodsfor the study, diagnosis, and treatment of traits, diseases andconditions that respond to the modulation of α-1 antitrypsin geneexpression and/or activity.

SEQUENCE SUBMISSION

The present application is being filed along with a Sequence Listing inelectronic format. The Sequence Listing is entitled“301937_94007_seq_listing_1JUL2014”, was created on Jul. 1, 2014, and is692 kb in size. The information in the electronic format of the SequenceListing is part of the present application and is incorporated herein byreference in its entirety.

BACKGROUND OF THE INVENTION

Alpha 1-antitrypsin (AAT or Serpina1) is a protease inhibitor belongingto the serpin superfamily. It is generally known as serum trypsininhibitor. Alpha 1-antitrypsin is also referred to as alpha-1 proteinaseinhibitor (A1PI) because it inhibits a wide variety of proteases(Gettins PG. Chem Rev 102: 4751-804). It protects tissues from enzymesof inflammatory cells, especially neutrophil elastase, and has areference range in blood of 1.5-3.5 gram/liter, but multi-fold elevatedlevels can occur upon acute inflammation (Kushner, Mackiewicz.Acute-phase glycoproteins: molecular biology, biochemistry and clinicalapplications (CRC Press). pp. 3-19). In the absence of AAT, neutrophilelastase is free to break down elastin, which contributes to theelasticity of the lungs, resulting in respiratory complications such asemphysema, or COPD (chronic obstructive pulmonary disease) in adults andcirrhosis in adults or children. Individuals with mutations in one orboth copies of the AAT gene can suffer from alpha-1 anti-trypsindeficiency, which presents as a risk of developing pulmonary emphysemaor chronic liver disease due to greater than normal elastase activity inthe lungs and liver.

In affected individuals, the deficiency in alpha-1 antitrypsin is adeficiency of wildtype, functional alpha-1 antitrypsin. However, in somecases that are relevant to the current invention, the individual isproducing significant quantities of alpha-1 antitrypsin, but aproportion of the alpha-1 antitrypsin protein being produced ismisfolded or contains mutations that compromise the functioning of theprotein. In some cases, the individual is producing misfolded proteinswhich cannot be properly transported from the site of synthesis to thesite of action within the body.

Liver disease resulting from alpha-1 antitrypsin deficiency can becaused by such misfolded proteins. Mutant forms of alpha-1 antitypsin(e.g., the common PiZ variant, which harbors a glutamate to lysinemutation at position 342 (position 366 in pre-processed form)) areproduced in liver cells (hepatocytes in the liver commonly produce alarge amount of circulating AAT), and in the misfolded configuration,such forms are not readily transported out of the cells. This leads to abuildup of misfolded protein in the liver cells (hepatocytes, wherethose with the largest burden of mutant Z protein can suffer a cascadeof intracellular damage that ultimately results in apoptosis; thischronic cycle of hepatocellular apoptosis and regeneration can lead tofibrosis and organ injury) and can cause one or more diseases ordisorders of the liver including, but not limited to, chronic liverdisease, liver inflammation, cirrhosis, liver fibrosis, and/orhepatocellular carcinoma.

There are currently few options for treating patients with liver diseaseassociated with alpha-1 antitrypsin deficiency, and such options includehepatitis vaccination, supportive care, and avoidance of injuriousagents (e.g., alcohol and NSAIDs), none of which provide a targetedtherapy. Replacement of alpha-1 antitrypsin has no impact on liverdisease in these patients but liver transplantation can be effective.

Double-stranded RNA (dsRNA) agents possessing strand lengths of 25 to 35nucleotides have been described as effective inhibitors of target geneexpression in mammalian cells (Rossi et al., U.S. Patent ApplicationNos. 2005/0244858 and US 2005/0277610). dsRNA agents of such length arebelieved to be processed by the Dicer enzyme of the RNA interference(RNAi) pathway, leading such agents to be termed “Dicer substrate siRNA”(“DsiRNA”) agents. Additional modified structures of DsiRNA agents werepreviously described (Rossi et al., U.S. Patent Application No.2007/0265220). Effective extended forms of Dicer substrates have alsorecently been described (Brown, U.S. Pat. No. 8,349,809 and US2010/0173974).

Provided herein are improved nucleic acid agents that target α-1antitrypsin. In particular, those targeting α-1 antitrypsin have beenspecifically exemplified.

BRIEF SUMMARY OF THE INVENTION

The present invention is directed to nucleic acid compositions thatreduce expression of α-1 antitrypsin. Such compositions contain nucleicacids such as double stranded RNA (“dsRNA”), and methods for preparingthem. The nucleic acids of the invention are capable of reducing theexpression of a target α-1 antitrypsin gene in a cell, either in vitroor in a mammalian subject.

In one aspect, the invention provides a nucleic acid having anoligonucleotide strand of 15-35 nucleotides in length that issufficiently complementary to a target α-1 antitrypsin mRNA sequence ofSEQ ID NOs: 991-1188 along at least 15 nucleotides of theoligonucleotide strand length to reduce α-1 antitrypsin target mRNAexpression when the nucleic acid is introduced into a mammalian cell.

In another aspect, the invention provides a nucleic acid having anoligonucleotide strand of 19-35 nucleotides in length that issufficiently complementary to a target α-1 antitrypsin mRNA sequence ofSEQ ID NOs: 991-1188 along at least 19 nucleotides of theoligonucleotide strand length to reduce α-1 antitrypsin target mRNAexpression when the nucleic acid is introduced into a mammalian cell.

In a further aspect, the invention provides a double stranded nucleicacid (dsNA) having first and second nucleic acid strands that includeRNA, where the first strand is 15-35 nucleotides in length and thesecond strand is 19-35 nucleotides in length and is sufficientlycomplementary to a target α-1 antitrypsin mRNA sequence of SEQ ID NOs:991-1188 along at least 15 nucleotides of the second oligonucleotidestrand length to reduce α-1 antitrypsin target mRNA expression when thedsNA is introduced into a mammalian cell.

In an additional aspect, the invention provides a dsNA having first andsecond nucleic acid strands, where the first strand is 15-35 nucleotidesin length and the second strand of the dsNA is 19-35 nucleotides inlength and is sufficiently complementary to a target α-1 antitrypsinmRNA sequence of SEQ ID NOs: 991-1188 along at least 19 nucleotides ofthe second oligonucleotide strand length to reduce α-1 antitrypsintarget mRNA expression when the dsNA is introduced into a mammaliancell.

In another aspect, the invention provides a dsNA having first and secondnucleic acid strands, where the first strand is 15-35 nucleotides inlength and the second strand of the dsNA is 19-35 nucleotides in lengthand is sufficiently complementary to a target α-1 antitrypsin mRNAsequence of SEQ ID NOs: 991-1188 along at least 19 nucleotides of thesecond oligonucleotide strand length to reduce α-1 antitrypsin targetmRNA expression, and where, starting from the 5′ end of the α-1antitrypsin mRNA sequence of SEQ ID NOs: 991-1188 (referred to asposition 1), mammalian Ago2 cleaves the mRNA at a site between positions9 and 10 of the sequence when the dsNA is introduced into a mammaliancell.

In a further aspect, the invention provides a dsNA molecule thatconsists of (a) a sense region and an antisense region, where the senseregion and the antisense region together form a duplex region consistingof 25-35 base pairs and the antisense region comprises a sequence thatis the complement of a sequence of any one (or more) of SEQ ID NOs:991-1188 and 1938-1968; and (b) from zero to two 3′ overhang regions,where each overhang region is six or fewer nucleotides in length, andwhere, starting from the 5′ end of the α-1 antitrypsin mRNA sequence ofSEQ ID NOs: 991-1188 and 1938-1968 (position 1), mammalian Ago2 cleavesthe mRNA at a site between positions 9 and 10 of the sequence when thedsNA is introduced into a mammalian cell.

In an additional aspect, the invention provides a dsNA having first andsecond nucleic acid strands and a duplex region of at least 25 basepairs, where the first strand is 25-34 nucleotides in length and thesecond strand of the dsNA is 26-35 nucleotides in length and includes1-5 single-stranded nucleotides at its 3′ terminus, where the secondoligonucleotide strand is sufficiently complementary to a target α-1antitrypsin mRNA sequence of SEQ ID NOs: 991-1188 and 1938-1968 along atleast 19 nucleotides of the second oligonucleotide strand length toreduce α-1 antitrypsin target gene expression when the dsNA isintroduced into a mammalian cell.

In another aspect, the invention provides a dsNA having first and secondnucleic acid strands and a duplex region of at least 25 base pairs,where the first strand is 25-34 nucleotides in length and the secondstrand of the dsNA is 26-35 nucleotides in length and comprises 1-5single-stranded nucleotides at its 3′ terminus, where the 3′ terminus ofthe first oligonucleotide strand and the 5′ terminus of the secondoligonucleotide strand form a blunt end, and the second oligonucleotidestrand is sufficiently complementary to a target α-1 antitrypsinsequence of SEQ ID NOs: 991-1188 and 1938-1968 along at least 19nucleotides of the second oligonucleotide strand length to reduce α-1antitrypsin mRNA expression when the dsNA is introduced into a mammaliancell.

In an additional aspect, the invention provides a nucleic acidpossessing an oligonucleotide strand of 15-35 nucleotides in length,where the oligonucleotide strand is hybridizable to a target α-1antitrypsin mRNA sequence of SEQ ID NOs: 991-1188 or 1938-1968 along atleast 15 nucleotides of the oligonucleotide strand length.

Another aspect of the invention provides a dsNA having first and secondnucleic acid strands that include RNA, where the first strand is 15-35nucleotides in length and the second strand of the dsNA is 19-35nucleotides in length, where the second oligonucleotide strand ishybridizable to a target α-1 antitrypsin mRNA sequence of SEQ ID NOs:991-1188 or 1938-1968 along at least 15 nucleotides of the secondoligonucleotide strand length.

A further aspect of the invention provides an in vivo hybridizationcomplex within a cell that includes an exogenous nucleic acid sequenceand a target alpha-1 antitrypsin mRNA sequence of SEQ ID NOs: 991-1188or 1938-1968.

An additional aspect of the invention provides an in vitro hybridizationcomplex within a cell that includes an exogenous nucleic acid sequenceand a target alpha-1 antitrypsin mRNA sequence of SEQ ID NOs: 991-1188or 1938-1968.

In one embodiment, the dsNA has a duplex region that is 19-21 basepairs, 21-25 base pairs or at least 25 base pairs in length.

In another embodiment, the second oligonucleotide strand includes 1-5single-stranded nucleotides at its 3′ terminus.

In an additional embodiment, the first strand is 25-35 nucleotides inlength. Optionally, the second strand is 25-35 nucleotides in length.

In another embodiment, the second oligonucleotide strand iscomplementary to target α-1 antitrypsin cDNA sequence GenBank AccessionNo. NM_000295.4 along at most 27 nucleotides of the secondoligonucleotide strand length.

In one embodiment, the dsNA or hybridization complex comprises amodified nucleotide. Optionally, the modified nucleotide residue is ofthe group consisting of 2′-O-methyl, 2′-methoxyethoxy, 2′-fluoro,2′-allyl, 2′-O-[2-(methylamino)-2-oxoethyl], 4′-thio,4′-CH2-O-2′-bridge, 4′-(CH2)2-O-2′-bridge, 2′-LNA, 2′-amino and2′-O—(N-methlycarbamate).

In a further embodiment, starting from the first nucleotide (position 1)at the 3′ terminus of the first oligonucleotide strand, position 1, 2 or3 is substituted with a modified nucleotide. Optionally, the modifiednucleotide residue of the 3′ terminus of the first strand is adeoxyribonucleotide, an acyclonucleotide or a fluorescent molecule. Incertain embodiments, position 1 of the 3′ terminus of the firstoligonucleotide strand is a deoxyribonucleotide.

In one embodiment, the first strand is 25 nucleotides in length and thesecond strand is 27 nucleotides in length. Optionally, the 3′ terminusof the first strand and the 5′ terminus of the second strand form ablunt end.

In another embodiment, starting from the 5′ end of a α-1 antitrypsinmRNA sequence of SEQ ID NOs: 991-1188 and 1938-1968 (position 1),mammalian Ago2 cleaves the mRNA at a site between positions 9 and 10 ofthe sequence, thereby reducing α-1 antitrypsin target mRNA expressionwhen the dsNA is introduced into a mammalian cell. Optionally, thesecond strand includes a sequence of SEQ ID NOs: 199-396 or 3493-3499.In certain embodiments, the first strand includes a sequence of SEQ IDNOs: 1-198.

In one embodiment, the dsNA includes a pair of first strand/secondstrand sequences of Table 2.

In a further embodiment, each of the first and the second strands has alength which is at least 26 nucleotides.

In one embodiment, nucleotides of the 1-5 single-stranded nucleotides ofthe 3′ terminus of the second strand include a modified nucleotide.Optionally, the modified nucleotide is a 2′-O-methyl ribonucleotide. Ina related embodiment, all nucleotides of the 1-5 single-strandednucleotides of the 3′ terminus of the second strand are modifiednucleotides. In certain embodiments, the 1-5 single-stranded nucleotidesof the 3′ terminus of the second strand are 1-4 nucleotides in length,are 1-3 nucleotides in length, or are 1-2 nucleotides in length. In arelated embodiment, the 1-5 single-stranded nucleotides of the 3′terminus of the second strand is two nucleotides in length and includesa 2′-O-methyl modified ribonucleotide.

In certain embodiments, the second oligonucleotide strand includes amodification pattern of AS-M1 to AS-M84, AS-M88 to AS-M96, AS-M210,AS-M1* to AS-M84*, AS-M88* to AS-M96* or AS-M210*.

Optionally, the first oligonucleotide strand includes a modificationpattern of SM1 to SM119 or SM250 to SM252.

In a further embodiment, each of the first and the second strands has alength which is at least 26 and at most 30 nucleotides.

Optionally, the dsNA is cleaved endogenously in the cell by Dicer.

In certain embodiments, a dsNA of the invention includes at least oneunlocked nucleobase analog (UNA). Optionally, the at least one UNA islocated in a 3′-overhang region, a 5′-overhang region, or both suchregions of the dsNA, optionally on the guide strand of the dsNA.

In some embodiments, a dsNA of the invention is attached to a dynamicpolyconjugate (DPC). In additional embodiments, a dsNA of the inventionis administered with a DPC, where optionally the dsNA and DPC are notattached.

In some embodiments, a dsNA of the invention is attached to a GalNAcmoiety (optionally, a tri-antennary GalNAc moiety) and/or to cholesterolor a cholesterol targeting ligand.

In certain embodiments, the amount of the nucleic acid sufficient toreduce expression of the target gene is 1 nanomolar or less, 200picomolar or less, 100 picomolar or less, 50 picomolar or less, 20picomolar or less, 10 picomolar or less, 5 picomolar or less, 2,picomolar or less or 1 picomolar or less in the environment of the cell.

In one embodiment, the dsNA possesses greater potency than a 21mer siRNAdirected to the identical at least 19 nucleotides of the target α-1antitrypsin mRNA in reducing target α-1 antitrypsin mRNA expression whenassayed in vitro in a mammalian cell at an effective concentration inthe environment of a cell of 1 nanomolar or less. In certainembodiments, knockdown efficacy and/or potency is measured at aconcentration of 1 nanomolar, 200 picomolar, 100 picomolar, 50picomolar, 20 picomolar, 10 picomolar, 5 picomolar, 2, picomolar or 1picomolar in the environment of a cell.

In another embodiment, the dsNA is sufficiently complementary to thetarget α-1 antitrypsin mRNA sequence to reduce α-1 antitrypsin targetmRNA expression by an amount (expressed by %) that is at least 10%, atleast 50%, at least 80-90%, at least 95%, at least 98%, or at least 99%when the dsNA is introduced into a mammalian cell.

In certain embodiments, the first and second strands are joined by achemical linker. Optionally, the 3′ terminus of the first strand and the5′ terminus of the second strand are joined by a chemical linker.

In one embodiment, a nucleotide of the second or first strand issubstituted with a modified nucleotide that directs the orientation ofDicer cleavage.

Optionally, the dsNA includes a deoxyribonucleotide, adideoxyribonucleotide, an acyclonucleotide, a 3′-deoxyadenosine(cordycepin), a 3′-azido-3′-deoxythymidine (AZT), a 2′,3′-dideoxyinosine(ddI), a 2′,3′-dideoxy-3′-thiacytidine (3TC), a2′,3′-didehydro-2′,3′-dideoxythymidine (d4T), a monophosphate nucleotideof 3′-azido-3′-deoxythymidine (AZT), a 2′,3′-dideoxy-3′-thiacytidine(3TC) and a monophosphate nucleotide of2′,3′-didehydro-2′,3′-dideoxythymidine (d4T), a 4-thiouracil, a5-bromouracil, a 5-iodouracil, a 5-(3-aminoallyl)-uracil, a 2′-O-alkylribonucleotide, a 2′-O-methyl ribonucleotide, a 2′-amino ribonucleotide,a 2′-fluoro ribonucleotide, or a locked nucleic acid.

In certain embodiments, the dsNA includes a phosphate backbonemodification that is a phosphonate, a phosphorothioate or aphosphotriester.

In one embodiment, the dsNA includes a morpholino nucleic acid or apeptide nucleic acid (PNA).

In one aspect, the invention provides a method for reducing expressionof a target α-1 antitrypsin gene in a mammalian cell involvingcontacting a mammalian cell in vitro with a dsNA of the invention in anamount sufficient to reduce expression of a target α-1 antitrypsin mRNAin the cell.

In one embodiment, target α-1 antitrypsin mRNA expression is reduced byat least 10%, at least 50% or at least 80-90%. Optionally, α-1antitrypsin mRNA levels are reduced by at least 90% at least 8 daysafter the cell is contacted with the dsNA. In certain embodiments, α-1antitrypsin mRNA levels are reduced by at least 70% at least 10 daysafter the cell is contacted with the dsNA.

In one aspect, the invention provides a method for reducing expressionof a target α-1 antitrypsin mRNA in a mammal involving administering anucleic acid of the invention to a mammal in an amount sufficient toreduce expression of a target α-1 antitrypsin mRNA in the mammal.

In certain embodiments, the nucleic acid is formulated in a lipidnanoparticle (LNP). In one embodiment, the nucleic acid is administeredat a dosage that is 1 microgram to 5 milligrams per kilogram of themammal per day, 100 micrograms to 0.5 milligrams per kilogram, 0.001 to0.25 milligrams per kilogram, 0.01 to 20 micrograms per kilogram, 0.01to 10 micrograms per kilogram, 0.10 to 5 micrograms per kilogram, or 0.1to 2.5 micrograms per kilogram.

In certain embodiments, the nucleic acid possesses greater potency than21mer siRNAs directed to the identical at least 19 nucleotides of thetarget α-1 antitrypsin mRNA in reducing target α-1 antitrypsin mRNAexpression when assayed in vitro in a mammalian cell at an effectiveconcentration in the environment of a cell of 1 nanomolar or less. Incertain embodiments, knockdown efficacy and/or potency is measured at aconcentration of 1 nanomolar, 200 picomolar, 100 picomolar, 50picomolar, 20 picomolar, 10 picomolar, 5 picomolar, 2, picomolar or 1picomolar in the environment of a cell.

In another embodiment, α-1 antitrypsin mRNA levels are reduced in atissue of the mammal by at least 70% at least 3 days after the dsNA isadministered to the mammal. Optionally, the tissue is liver tissue.

In certain embodiments, administering includes intravenous injection,intramuscular injection, intraperitoneal injection, infusion,subcutaneous injection, transdermal, aerosol, rectal, vaginal, topical,oral or inhaled delivery.

In another aspect, the invention provides a method for treating orpreventing a liver disease or disorder in a subject that involvesadministering a dsNA of the invention to the subject in an amountsufficient to treat or prevent the liver disease or disorder in thesubject.

In one embodiment, the liver disease or disorder is a chronic liverdisease, liver inflammation, cirrhosis, liver fibrosis or hepatocellularcarcinoma. Optionally, the subject is human.

In a further aspect, the invention provides a formulation containing anucleic acid of the invention present in an amount effective to reducetarget α-1 antitrypsin mRNA levels when the nucleic acid is introducedinto a mammalian cell in vitro by at least 10%, at least 50% or at least80-90%.

In one embodiment, the effective amount is 1 nanomolar or less, 200picomolar or less, 100 picomolar or less, 50 picomolar or less, 20picomolar or less, 10 picomolar or less, 5 picomolar or less, 2,picomolar or less or 1 picomolar or less in the environment of the cell.In certain embodiments, knockdown efficacy is measured at aconcentration of 1 nanomolar, 200 picomolar, 100 picomolar, 50picomolar, 20 picomolar, 10 picomolar, 5 picomolar, 2, picomolar or 1picomolar in the environment of a cell.

In another aspect, the invention provides a formulation including thedsNA of the invention present in an amount effective to reduce targetα-1 antitrypsin mRNA levels when the dsNA is introduced into a cell of amammalian subject by at least 10%, at least 50% or at least 80-90%.Optionally, the effective amount is a dosage of 1 microgram to 5milligrams per kilogram of the subject per day, 100 micrograms to 0.5milligrams per kilogram, 0.001 to 0.25 milligrams per kilogram, 0.01 to20 micrograms per kilogram, 0.01 to 10 micrograms per kilogram, 0.10 to5 micrograms per kilogram, or 0.1 to 2.5 micrograms per kilogram.

In an additional aspect, the invention provides a mammalian cellcontaining a nucleic acid of the invention.

In a further aspect, the invention provides a pharmaceutical compositioncontaining a nucleic acid of the invention and a pharmaceuticallyacceptable carrier.

In another aspect, the invention provides a kit that includes a nucleicacid of the invention and instructions for its use.

In an additional aspect, the invention provides a composition possessingα-1 antitrypsin inhibitory activity that consists essentially of anucleic acid of the invention.

Another aspect of the invention provides a method of hybridizing anexogenous nucleic acid to mRNA in a cell that involves introducing intothe cell an exogenous nucleic acid sequence and hybridizing theexogenous nucleic acid to a target alpha-1 antitrypsin mRNA sequencethat is a sequence of SEQ ID NOs: 991-1188 or 1938-1968.

A further aspect of the invention provides a method of treating anindividual with a liver or lung disease or disorder that involvesintroducing into cells of the individual an exogenous nucleic acidsequence and hybridizing the exogenous nucleic acid to a target alpha-1antitrypsin mRNA sequence of SEQ ID NOs: 991-1188 or 1938-1968.

An additional aspect of the invention provides a method of forming an invivo hybridization complex within a cell that involves introducing intothe cell an exogenous nucleic acid sequence and hybridizing theexogenous nucleic acid to a target alpha-1 antitrypsin mRNA sequence ofSEQ ID NOs: 991-1188 or 1938-1968.

A further aspect of the invention provides a method of inhibitingtranslation of a target mRNA into a protein within a cell that involvesintroducing into the cell an exogenous nucleic acid sequence andhybridizing the exogenous nucleic acid to a target alpha-1 antitrypsinmRNA sequence of SEQ ID NOs: 991-1188 or 1938-1968, complexing theexogenous nucleic acid with RISC, and cleaving the mRNA.

In one embodiment, the exogenous nucleic acid is complexed with RISC. Ina related embodiment, the RISC cleaves the mRNA.

Another aspect of the invention provides a “single strand-extended”(here, guide strand-extended, at the 5′ end) dsNA. Specifically, thisaspect of the invention provides a dsNA having first and second nucleicacid strands that include RNA, where the first strand is 15-35nucleotides in length and the second strand is at least 35 nucleotidesin length, optionally includes a second strand sequence having at least25 nucleotides of a sequence of SEQ ID NOs: 3493-3499 and issufficiently complementary to a target α-1 antitrypsin mRNA sequence ofSEQ ID NOs: 991-1188 along at least 15 nucleotides of the secondoligonucleotide strand length to reduce α-1 antitrypsin target mRNAexpression when the dsNA is introduced into a mammalian cell.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the structures of exemplary DsiRNA agents of the inventiontargeting a site in the α-1 antitrypsin RNA referred to herein as the“α-1 antitrypsin-506” target site. UPPER case=unmodified RNA, lowercase=DNA, Bold=mismatch base pair nucleotides; arrowheads indicateprojected Dicer enzyme cleavage sites; dashed line indicates sensestrand (top strand) sequences corresponding to the projected Argonaute 2(Ago2) cleavage site within the targeted α-1 antitrypsin sequence.

FIGS. 2A to 2D present primary screen data showing DsiRNA-mediatedknockdown of human α-1 antitrypsin (FIGS. 2A and 2B) and mouse α-1antitrypsin (FIGS. 2C and 2D) in human (Huh7) and mouse (AML12) cells,respectively. For each DsiRNA tested, two independent qPCR ampliconswere assayed (in human cells, amplicons “462-563” and “1811-1910” wereassayed, while in mouse cells, amplicons “331-462” and “1532-1662” wereassayed).

FIGS. 3A to 3H show histograms of human and mouse α-1 antitrypsininhibitory efficacies observed for indicated DsiRNAs. “P1” indicatesphase 1 (primary screen), while “P2” indicates phase 2. In phase 1,DsiRNAs were tested at 1 nM in the environment of Huh7 cells (human cellassays; FIGS. 3A to 3D) or mouse cells (AML12 cell assays; FIGS. 3E to3H). In phase 2, DsiRNAs were tested at 1 nM, 0.1 nM and 0.03 nM in theenvironment of Huh7 cells. Individual bars represent average human(FIGS. 3A to 3D) or mouse (FIGS. 3E to 3H) α-1 antitrypsin levelsobserved in triplicate, with standard errors shown. Human α-1antitrypsin levels were normalized to HPRT and SFRS9 levels, while mouseα-1 antitrypsin levels were normalized to HPRT and Rpl23 levels.

FIGS. 4A to 4F present data showing levels of α-1 antitrypsin knockdownobserved for 24 α-1 antitrypsin-targeting duplex sequences possessing arange of guide strand 2′-O-methyl modifications and a single passengerstrand 2′-O-methyl modification pattern, as depicted in FIGS. 4A and 4B.Bar graphs of FIGS. 4C to 4F show efficacy data for the 24 independentα-1 antitrypsin-targeting DsiRNAs across different, indicated guide(antisense) strand 2′-O-methyl modification patterns in human Huh7 cellsat 0.03 nM, 0.1 nM and at 1 nM.

FIGS. 5A to 5H present data obtained in an expanded modified duplexscreen. FIGS. 5A to 5D depict 2′-O-methyl modification patterns of bothpassenger and guide strands of tested duplexes (with FIG. 5D showingmodification patterns of individual strands), while FIGS. 5E to 5H showhistograms of human α-1 antitrypsin inhibitory efficacies observed forindicated DsiRNAs in human cells. “P4” indicates phase 4 (expandedmodified duplex screen). In the expanded modification screen, DsiRNAswere tested at 0.03 nM, 0.1 nM and at 1 nM in the environment of humanHuh7 cells. Individual bars represent average human α-1 antitrypsinlevels observed in triplicate, with standard errors shown. Human α-1antitrypsin levels were normalized to HPRT and SFRS9 levels.

FIGS. 6A and 6B demonstrate the robust α-1 antitrypsin knockdownefficacy of guide strand “extended” forms of α-1 antitrypsin-targetingDsiRNAs of the invention. FIG. 6A shows the specific sequences of eachof the eight extended DsiRNAs tested (corresponding SEQ ID NOs areindicated at right for sense and antisense sequences, respectively).FIG. 6B shows IC₅₀ curves obtained for each of the eight guide strand“extended” forms of α-1 antitrypsin-targeting DsiRNAs that were tested(“C121” represents a control DsiRNA that does not target α-1antitrypsin).

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to compositions that contain nucleicacids, for example double stranded RNA (“dsRNA”), and methods forpreparing them, that are capable of reducing the level and/or expressionof the α-1 antitrypsin gene in vivo or in vitro. One of the strands ofthe dsRNA contains a region of nucleotide sequence that has a lengththat ranges from 19 to 35 nucleotides that can direct the destructionand/or translational inhibition of the targeted α-1 antitrypsintranscript.

Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the meaning commonly understood by a person skilled in the art towhich this invention belongs. The following references provide one ofskill with a general definition of many of the terms used in thisinvention: Singleton et al., Dictionary of Microbiology and MolecularBiology (2nd ed. 1994); The Cambridge Dictionary of Science andTechnology (Walker ed., 1988); The Glossary of Genetics, 5th Ed., R.Rieger et al. (eds.), Springer Verlag (1991); and Hale & Marham, TheHarper Collins Dictionary of Biology (1991). As used herein, thefollowing terms have the meanings ascribed to them below, unlessspecified otherwise.

The present invention features one or more DsiRNA molecules that canmodulate (e.g., inhibit) α-1 antitrypsin expression. The DsiRNAs of theinvention optionally can be used in combination with modulators of othergenes and/or gene products associated with the maintenance ordevelopment of diseases or disorders associated with α-1 antitrypsinmisregulation (e.g., tumor formation and/or growth, etc.). The DsiRNAagents of the invention modulate α-1 antitrypsin RNAs such as thosecorresponding to the cDNA sequences referred to by GenBank AccessionNos. NM_000295.4 (human α-1 antitrypsin) and NM_009246.3 (mouseSerpina1d), which are referred to herein generally as “α-1 antitrypsin.”

The below description of the various aspects and embodiments of theinvention is provided with reference to exemplary α-1 antitrypsin RNAs,generally referred to herein as α-1 antitrypsin. However, such referenceis meant to be exemplary only and the various aspects and embodiments ofthe invention are also directed to alternate α-1 antitrypsin RNAs, suchas mutant α-1 antitrypsin RNAs or additional α-1 antitrypsin splicevariants. Certain aspects and embodiments are also directed to othergenes involved in α-1 antitrypsin pathways, including genes whosemisregulation acts in association with that of α-1 antitrypsin (or isaffected or affects α-1 antitrypsin regulation) to produce phenotypiceffects that may be targeted for treatment (e.g., tumor formation and/orgrowth, etc.). BAK1, Noxa, BCL2L11, Bcl-2-associated death promoter,PCNA, DAD1, TNKS and BH3 interacting domain death agonist are examplesof genes that interact with α-1 antitrypsin. Such additional genes,including those of pathways that act in coordination with α-1antitrypsin, can be targeted using dsRNA and the methods describedherein for use of α-1 antitrypsin-targeting dsRNAs. Thus, the inhibitionand the effects of such inhibition of the other genes can be performedas described herein.

The term “α-1 antitrypsin” refers to nucleic acid sequences encoding aα-1 antitrypsin protein, peptide, or polypeptide (e.g., α-1 antitrypsintranscripts, such as the sequences of α-1 antitrypsin Genbank AccessionNos. NM_000295.4 and NM_009246.3). In certain embodiments, the term “α-1antitrypsin” is also meant to include other α-1 antitrypsin encodingsequence, such as other α-1 antitrypsin isoforms, mutant α-1 antitrypsingenes, splice variants of α-1 antitrypsin genes, and α-1 antitrypsingene polymorphisms. The term “α-1 antitrypsin” is also used to refer tothe polypeptide gene product of an α-1 antitrypsin gene/transcript,e.g., an α-1 antitrypsin protein, peptide, or polypeptide, such as thoseencoded by α-1 antitrypsin Genbank Accession Nos. NP_000286.3 andNP_033272.1.

As used herein, a “α-1 antitrypsin-associated disease or disorder”refers to a disease or disorder known in the art to be associated withaltered α-1 antitrypsin expression, level and/or activity. Notably, a“α-1 antitrypsin-associated disease or disorder” includes diseases ordisorders of the liver including, but not limited to, chronic liverdisease, liver inflammation, cirrhosis, liver fibrosis, and/orhepatocellular carcinoma.

An anti-α-1 antitrypsin dsRNA of the invention is deemed to possess “α-1antitrypsin inhibitory activity” if a statistically significantreduction in α-1 antitrypsin RNA (or when the α-1 antitrypsin protein isassessed, α-1 antitrypsin protein levels) is seen when an anti-α-1antitrypsin dsRNA of the invention is administered to a system (e.g.,cell-free in vitro system), cell, tissue or organism, as compared to aselected control. The distribution of experimental values and the numberof replicate assays performed will tend to dictate the parameters ofwhat levels of reduction in α-1 antitrypsin RNA (either as a % or inabsolute terms) is deemed statistically significant (as assessed bystandard methods of determining statistical significance known in theart). However, in certain embodiments, “α-1 antitrypsin inhibitoryactivity” is defined based upon a % or absolute level of reduction inthe level of α-1 antitrypsin in a system, cell, tissue or organism. Forexample, in certain embodiments, a dsRNA of the invention is deemed topossess α-1 antitrypsin inhibitory activity if at least a 5% reductionor at least a 10% reduction in α-1 antitrypsin RNA is observed in thepresence of a dsRNA of the invention relative to α-1 antitrypsin levelsseen for a suitable control. (For example, in vivo α-1 antitrypsinlevels in a tissue and/or subject can, in certain embodiments, be deemedto be inhibited by a dsRNA agent of the invention if, e.g., a 5% or 10%reduction in α-1 antitrypsin levels is observed relative to a control.)In certain other embodiments, a dsRNA of the invention is deemed topossess α-1 antitrypsin inhibitory activity if α-1 antitrypsin RNAlevels are observed to be reduced by at least 15% relative to a selectedcontrol, by at least 20% relative to a selected control, by at least 25%relative to a selected control, by at least 30% relative to a selectedcontrol, by at least 35% relative to a selected control, by at least 40%relative to a selected control, by at least 45% relative to a selectedcontrol, by at least 50% relative to a selected control, by at least 55%relative to a selected control, by at least 60% relative to a selectedcontrol, by at least 65% relative to a selected control, by at least 70%relative to a selected control, by at least 75% relative to a selectedcontrol, by at least 80% relative to a selected control, by at least 85%relative to a selected control, by at least 90% relative to a selectedcontrol, by at least 95% relative to a selected control, by at least 96%relative to a selected control, by at least 97% relative to a selectedcontrol, by at least 98% relative to a selected control or by at least99% relative to a selected control. In some embodiments, completeinhibition of α-1 antitrypsin is required for a dsRNA to be deemed topossess α-1 antitrypsin inhibitory activity. In certain models (e.g.,cell culture), a dsRNA is deemed to possess α-1 antitrypsin inhibitoryactivity if at least a 50% reduction in α-1 antitrypsin levels isobserved relative to a suitable control. In certain other embodiments, adsRNA is deemed to possess α-1 antitrypsin inhibitory activity if atleast an 80% reduction in α-1 antitrypsin levels is observed relative toa suitable control.

By way of specific example, in Example 2 below, a series of DsiRNAstargeting α-1 antitrypsin were tested for the ability to reduce α-1antitrypsin mRNA levels in human Huh7 or mouse AML12 cells in vitro, at1 nM concentrations in the environment of such cells and in the presenceof a transfection agent (Lipofectamine™ RNAiMAX, Invitrogen). WithinExample 2 below, α-1 antitrypsin inhibitory activity was ascribed tothose DsiRNAs that were observed to effect at least a 70% reduction ofα-1 antitrypsin mRNA levels under the assayed conditions. It iscontemplated that α-1 antitrypsin inhibitory activity could also beattributed to a dsRNA under either more or less stringent conditionsthan those employed for Example 2 below, even when the same or a similarassay and conditions are employed. For example, in certain embodiments,a tested dsRNA of the invention is deemed to possess α-1 antitrypsininhibitory activity if at least a 10% reduction, at least a 20%reduction, at least a 30% reduction, at least a 40% reduction, at leasta 50% reduction, at least a 60% reduction, at least a 75% reduction, atleast an 80% reduction, at least an 85% reduction, at least a 90%reduction, or at least a 95% reduction in α-1 antitrypsin mRNA levels isobserved in a mammalian cell line in vitro at 1 nM dsRNA concentrationor lower in the environment of a cell, relative to a suitable control.

Use of other endpoints for determination of whether a double strandedRNA of the invention possesses α-1 antitrypsin inhibitory activity isalso contemplated. Specifically, in one embodiment, in addition to or asan alternative to assessing α-1 antitrypsin mRNA levels, the ability ofa tested dsRNA to reduce α-1 antitrypsin protein levels (e.g., at 48hours after contacting a mammalian cell in vitro or in vivo) isassessed, and a tested dsRNA is deemed to possess α-1 antitrypsininhibitory activity if at least a 10% reduction, at least a 20%reduction, at least a 30% reduction, at least a 40% reduction, at leasta 50% reduction, at least a 60% reduction, at least a 70% reduction, atleast a 75% reduction, at least an 80% reduction, at least an 85%reduction, at least a 90% reduction, or at least a 95% reduction in α-1antitrypsin protein levels is observed in a mammalian cell contactedwith the assayed double stranded RNA in vitro or in vivo, relative to asuitable control. Additional endpoints contemplated include, e.g.,assessment of a phenotype associated with reduction of α-1 antitrypsinlevels—e.g., reduction of chronic liver disease, liver inflammation,cirrhosis, liver fibrosis, and/or hepatocellular carcinoma, as assesseddirectly or via assessment of appropriate markers and/or indicators ofsuch liver disease or disorder. α-1 antitrypsin inhibitory activity canalso be evaluated over time (duration) and over concentration ranges(potency), with assessment of what constitutes a dsRNA possessing α-1antitrypsin inhibitory activity adjusted in accordance withconcentrations administered and duration of time followingadministration. Thus, in certain embodiments, a dsRNA of the inventionis deemed to possess α-1 antitrypsin inhibitory activity if at least a50% reduction in α-1 antitrypsin activity is observed/persists at aduration of time of 2 hours, 5 hours, 10 hours, 1 day, 2 days, 3 days, 4days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days or more afteradministration of the dsRNA to a cell or organism. In additionalembodiments, a dsRNA of the invention is deemed to be a potent α-1antitrypsin inhibitory agent if α-1 antitrypsin inhibitory activity(e.g., in certain embodiments, at least 50% inhibition of α-1antitrypsin) is observed at a concentration of 1 nM or less, 500 pM orless, 200 pM or less, 100 pM or less, 50 pM or less, 20 pM or less, 10pM or less, 5 pM or less, 2 pM or less or even 1 pM or less in theenvironment of a cell, for example, within an in vitro assay for α-1antitrypsin inhibitory activity as described herein. In certainembodiments, a potent α-1 antitrypsin inhibitory dsRNA of the inventionis defined as one that is capable of α-1 antitrypsin inhibitory activity(e.g., in certain embodiments, at least 20% reduction of α-1 antitrypsinlevels) at a formulated concentration of 10 mg/kg or less whenadministered to a subject in an effective delivery vehicle (e.g., aneffective lipid nanoparticle formulation). Preferably, a potent α-1antitrypsin inhibitory dsRNA of the invention is defined as one that iscapable of α-1 antitrypsin inhibitory activity (e.g., in certainembodiments, at least 50% reduction of α-1 antitrypsin levels) at aformulated concentration of 5 mg/kg or less when administered to asubject in an effective delivery vehicle. More preferably, a potent α-1antitrypsin inhibitory dsRNA of the invention is defined as one that iscapable of α-1 antitrypsin inhibitory activity (e.g., in certainembodiments, at least 50% reduction of α-1 antitrypsin levels) at aformulated concentration of 5 mg/kg or less when administered to asubject in an effective delivery vehicle. Optionally, a potent α-1antitrypsin inhibitory dsRNA of the invention is defined as one that iscapable of α-1 antitrypsin inhibitory activity (e.g., in certainembodiments, at least 50% reduction of α-1 antitrypsin levels) at aformulated concentration of 2 mg/kg or less, or even 1 mg/kg or less,when administered to a subject in an effective delivery vehicle.Exemplary discrete formulated concentrations of α-1antitrypsin-targeting RNAi agents of the invention include about 5mg/kg, about 2 mg/kg, about 1 mg/kg, about 500 mg/kg, about 250 mg/kg,about 100 mg/kg, about 50 mg/kg, about 25 mg/kg, about 10 μg/kg, about 5μg/kg, about 2.5 μg/kg, about 1 μg/kg, about 500 ng/kg, about 250 ng/kg,about 100 ng/kg, about 50 ng/kg, about 25 ng/kg, about 10 ng/kg, about 5ng/kg, about 2.5 ng/kg, about 1 ng/kg and about 500 pg/kg.

About: As used herein, the term “about” means +/−10% of the recitedvalue. Use of “about” is contemplated in reference to all ranges andvalues recited herein.

In certain embodiments, the phrase “consists essentially of” is used inreference to the anti-α-1 antitrypsin dsRNAs of the invention. In somesuch embodiments, “consists essentially of” refers to a composition thatcomprises a dsRNA of the invention which possesses at least a certainlevel of α-1 antitrypsin inhibitory activity (e.g., at least 50% α-1antitrypsin inhibitory activity) and that also comprises one or moreadditional components and/or modifications that do not significantlyimpact the α-1 antitrypsin inhibitory activity of the dsRNA. Forexample, in certain embodiments, a composition “consists essentially of”a dsRNA of the invention where modifications of the dsRNA of theinvention and/or dsRNA-associated components of the composition do notalter the α-1 antitrypsin inhibitory activity (optionally includingpotency or duration of α-1 antitrypsin inhibitory activity) by greaterthan 3%, greater than 5%, greater than 10%, greater than 15%, greaterthan 20%, greater than 25%, greater than 30%, greater than 35%, greaterthan 40%, greater than 45%, or greater than 50% relative to the dsRNA ofthe invention in isolation. In certain embodiments, a composition isdeemed to consist essentially of a dsRNA of the invention even if moredramatic reduction of α-1 antitrypsin inhibitory activity (e.g., 80%reduction, 90% reduction, etc. in efficacy, duration and/or potency)occurs in the presence of additional components or modifications, yetwhere α-1 antitrypsin inhibitory activity is not significantly elevated(e.g., observed levels of α-1 antitrypsin inhibitory activity are within10% those observed for the dsRNA of the invention) in the presence ofadditional components and/or modifications.

As used herein, the term “nucleic acid” refers to deoxyribonucleotides,ribonucleotides, or modified nucleotides, and polymers thereof insingle- or double-stranded form. The term encompasses nucleic acidscontaining known nucleotide analogs or modified backbone residues orlinkages, which are synthetic, naturally occurring, and non-naturallyoccurring, which have similar binding properties as the referencenucleic acid, and which are metabolized in a manner similar to thereference nucleotides. Examples of such analogs include, withoutlimitation, phosphorothioates, phosphoramidates, methyl phosphonates,chiral-methyl phosphonates, 2-O-methyl ribonucleotides, peptide-nucleicacids (PNAs) and unlocked nucleic acids (UNAs or unlocked nucleobaseanalogs; see, e.g., Jensen et al. Nucleic Acids Symposium Series 52:133-4), and derivatives thereof.

As used herein, “nucleotide” is used as recognized in the art to includethose with natural bases (standard), and modified bases well known inthe art. Such bases are generally located at the 1′ position of anucleotide sugar moiety. Nucleotides generally comprise a base, sugarand a phosphate group. The nucleotides can be unmodified or modified atthe sugar, phosphate and/or base moiety, (also referred tointerchangeably as nucleotide analogs, modified nucleotides, non-naturalnucleotides, non-standard nucleotides and other; see, e.g., Usman andMcSwiggen, supra; Eckstein, et al., International PCT Publication No. WO92/07065; Usman et al, International PCT Publication No. WO 93/15187;Uhlman & Peyman, supra, all are hereby incorporated by referenceherein). There are several examples of modified nucleic acid bases knownin the art as summarized by Limbach, et al, Nucleic Acids Res. 22:2183,1994. Some of the non-limiting examples of base modifications that canbe introduced into nucleic acid molecules include, hypoxanthine, purine,pyridin-4-one, pyridin-2-one, phenyl, pseudouracil, 2,4,6-trimethoxybenzene, 3-methyl uracil, dihydrouridine, naphthyl, aminophenyl,5-alkylcytidines (e.g., 5-methylcytidine), 5-alkyluridines (e.g.,ribothymidine), 5-halouridine (e.g., 5-bromouridine) or 6-azapyrimidinesor 6-alkylpyrimidines (e.g. 6-methyluridine), propyne, and others(Burgin, et al., Biochemistry 35:14090, 1996; Uhlman & Peyman, supra).By “modified bases” in this aspect is meant nucleotide bases other thanadenine, guanine, cytosine and uracil at 1′ position or theirequivalents.

As used herein, “modified nucleotide” refers to a nucleotide that hasone or more modifications to the nucleoside, the nucleobase, pentosering, or phosphate group. For example, modified nucleotides excluderibonucleotides containing adenosine monophosphate, guanosinemonophosphate, uridine monophosphate, and cytidine monophosphate anddeoxyribonucleotides containing deoxyadenosine monophosphate,deoxyguanosine monophosphate, deoxythymidine monophosphate, anddeoxycytidine monophosphate. Modifications include those naturallyoccurring that result from modification by enzymes that modifynucleotides, such as methyltransferases. Modified nucleotides alsoinclude synthetic or non-naturally occurring nucleotides. Synthetic ornon-naturally occurring modifications in nucleotides include those with2′ modifications, e.g., 2′-methoxyethoxy, 2′-fluoro, 2′-allyl,2′-O-[2-(methylamino)-2-oxoethyl], 4′-thio, 4′-CH₂—O-2′-bridge,4′-(CH₂)₂—O-2′-bridge, 2′-LNA or other bicyclic or “bridged” nucleosideanalog, and 2′-O—(N-methylcarbamate) or those comprising base analogs.In connection with 2′-modified nucleotides as described for the presentdisclosure, by “amino” is meant 2′-NH₂ or 2′-O—NH₂, which can bemodified or unmodified. Such modified groups are described, e.g., inEckstein et al., U.S. Pat. No. 5,672,695 and Matulic-Adamic et al., U.S.Pat. No. 6,248,878. “Modified nucleotides” of the instant invention canalso include nucleotide analogs as described above.

In reference to the nucleic acid molecules of the present disclosure,modifications may exist upon these agents in patterns on one or bothstrands of the double stranded ribonucleic acid (dsRNA). As used herein,“alternating positions” refers to a pattern where every other nucleotideis a modified nucleotide or there is an unmodified nucleotide (e.g., anunmodified ribonucleotide) between every modified nucleotide over adefined length of a strand of the dsRNA (e.g., 5′-MNMNMN-3′;3′-MNMNMN-5′; where M is a modified nucleotide and N is an unmodifiednucleotide). The modification pattern starts from the first nucleotideposition at either the 5′ or 3′ terminus according to a positionnumbering convention, e.g., as described herein (in certain embodiments,position 1 is designated in reference to the terminal residue of astrand following a projected Dicer cleavage event of a DsiRNA agent ofthe invention; thus, position 1 does not always constitute a 3′ terminalor 5′ terminal residue of a pre-processed agent of the invention). Thepattern of modified nucleotides at alternating positions may run thefull length of the strand, but in certain embodiments includes at least4, 6, 8, 10, 12, 14 nucleotides containing at least 2, 3, 4, 5, 6 or 7modified nucleotides, respectively. As used herein, “alternating pairsof positions” refers to a pattern where two consecutive modifiednucleotides are separated by two consecutive unmodified nucleotides overa defined length of a strand of the dsRNA (e.g., 5′-MMNNMMNNMMNN-3′;3′-MMNNMMNNMMNN-5′; where M is a modified nucleotide and N is anunmodified nucleotide). The modification pattern starts from the firstnucleotide position at either the 5′ or 3′ terminus according to aposition numbering convention such as those described herein. Thepattern of modified nucleotides at alternating positions may run thefull length of the strand, but preferably includes at least 8, 12, 16,20, 24, 28 nucleotides containing at least 4, 6, 8, 10, 12 or 14modified nucleotides, respectively. It is emphasized that the abovemodification patterns are exemplary and are not intended as limitationson the scope of the invention.

As used herein, “base analog” refers to a heterocyclic moiety which islocated at the 1′ position of a nucleotide sugar moiety in a modifiednucleotide that can be incorporated into a nucleic acid duplex (or theequivalent position in a nucleotide sugar moiety substitution that canbe incorporated into a nucleic acid duplex). In the dsRNAs of theinvention, a base analog is generally either a purine or pyrimidine baseexcluding the common bases guanine (G), cytosine (C), adenine (A),thymine (T), and uracil (U). Base analogs can duplex with other bases orbase analogs in dsRNAs. Base analogs include those useful in thecompounds and methods of the invention., e.g., those disclosed in U.S.Pat. Nos. 5,432,272 and 6,001,983 to Benner and US Patent PublicationNo. 20080213891 to Manoharan, which are herein incorporated byreference. Non-limiting examples of bases include hypoxanthine (I),xanthine (X), 3β-D-ribofuranosyl-(2,6-diaminopyrimidine) (K),3-β-D-ribofuranosyl-(1-methyl-pyrazolo[4,3-d]pyrimidine-5,7(4H,6H)-dione)(P), iso-cytosine (iso-C), iso-guanine (iso-G),1-β-D-ribofuranosyl-(5-nitroindole),1-β-D-ribofuranosyl-(3-nitropyrrole), 5-bromouracil, 2-aminopurine,4-thio-dT, 7-(2-thienyl)-imidazo[4,5-b]pyridine (Ds) andpyrrole-2-carbaldehyde (Pa), 2-amino-6-(2-thienyl)purine (S),2-oxopyridine (Y), difluorotolyl, 4-fluoro-6-methylbenzimidazole,4-methylbenzimidazole, 3-methyl isocarbostyrilyl, 5-methylisocarbostyrilyl, and 3-methyl-7-propynyl isocarbostyrilyl,7-azaindolyl, 6-methyl-7-azaindolyl, imidizopyridinyl,9-methyl-imidizopyridinyl, pyrrolopyrizinyl, isocarbostyrilyl,7-propynyl isocarbostyrilyl, propynyl-7-azaindolyl,2,4,5-trimethylphenyl, 4-methylindolyl, 4,6-dimethylindolyl, phenyl,napthalenyl, anthracenyl, phenanthracenyl, pyrenyl, stilbenzyl,tetracenyl, pentacenyl, and structural derivates thereof (Schweitzer etal., J. Org. Chem., 59:7238-7242 (1994); Berger et al., Nucleic AcidsResearch, 28(15):2911-2914 (2000); Moran et al., J. Am. Chem. Soc.,119:2056-2057 (1997); Morales et al., J. Am. Chem. Soc., 121:2323-2324(1999); Guckian et al., J. Am. Chem. Soc., 118:8182-8183 (1996); Moraleset al., J. Am. Chem. Soc., 122(6):1001-1007 (2000); McMinn et al., J.Am. Chem. Soc., 121:11585-11586 (1999); Guckian et al., J. Org. Chem.,63:9652-9656 (1998); Moran et al., Proc. Natl. Acad. Sci.,94:10506-10511 (1997); Das et al., J. Chem. Soc., Perkin Trans.,1:197-206 (2002); Shibata et al., J. Chem. Soc., Perkin Trans., 1:1605-1611 (2001); Wu et al., J. Am. Chem. Soc., 122(32):7621-7632(2000); O'Neill et al., J. Org. Chem., 67:5869-5875 (2002); Chaudhuri etal., J. Am. Chem. Soc., 117:10434-10442 (1995); and U.S. Pat. No.6,218,108.). Base analogs may also be a universal base.

As used herein, “universal base” refers to a heterocyclic moiety locatedat the 1′ position of a nucleotide sugar moiety in a modifiednucleotide, or the equivalent position in a nucleotide sugar moietysubstitution, that, when present in a nucleic acid duplex, can bepositioned opposite more than one type of base without altering thedouble helical structure (e.g., the structure of the phosphatebackbone). Additionally, the universal base does not destroy the abilityof the single stranded nucleic acid in which it resides to duplex to atarget nucleic acid. The ability of a single stranded nucleic acidcontaining a universal base to duplex a target nucleic can be assayed bymethods apparent to one in the art (e.g., UV absorbance, circulardichroism, gel shift, single stranded nuclease sensitivity, etc.).Additionally, conditions under which duplex formation is observed may bevaried to determine duplex stability or formation, e.g., temperature, asmelting temperature (Tm) correlates with the stability of nucleic acidduplexes. Compared to a reference single stranded nucleic acid that isexactly complementary to a target nucleic acid, the single strandednucleic acid containing a universal base forms a duplex with the targetnucleic acid that has a lower Tm than a duplex formed with thecomplementary nucleic acid. However, compared to a reference singlestranded nucleic acid in which the universal base has been replaced witha base to generate a single mismatch, the single stranded nucleic acidcontaining the universal base forms a duplex with the target nucleicacid that has a higher Tm than a duplex formed with the nucleic acidhaving the mismatched base.

Some universal bases are capable of base pairing by forming hydrogenbonds between the universal base and all of the bases guanine (G),cytosine (C), adenine (A), thymine (T), and uracil (U) under base pairforming conditions. A universal base is not a base that forms a basepair with only one single complementary base. In a duplex, a universalbase may form no hydrogen bonds, one hydrogen bond, or more than onehydrogen bond with each of G, C, A, T, and U opposite to it on theopposite strand of a duplex. Preferably, the universal bases does notinteract with the base opposite to it on the opposite strand of aduplex. In a duplex, base pairing between a universal base occurswithout altering the double helical structure of the phosphate backbone.A universal base may also interact with bases in adjacent nucleotides onthe same nucleic acid strand by stacking interactions. Such stackinginteractions stabilize the duplex, especially in situations where theuniversal base does not form any hydrogen bonds with the base positionedopposite to it on the opposite strand of the duplex. Non-limitingexamples of universal-binding nucleotides include inosine,1-β-D-ribofuranosyl-5-nitroindole, and/or1-β-D-ribofuranosyl-3-nitropyrrole (US Pat. Appl. Publ. No. 20070254362to Quay et al.; Van Aerschot et al., An acyclic 5-nitroindazolenucleoside analogue as ambiguous nucleoside. Nucleic Acids Res. 1995Nov. 11; 23(21):4363-70; Loakes et al., 3-Nitropyrrole and 5-nitroindoleas universal bases in primers for DNA sequencing and PCR. Nucleic AcidsRes. 1995 Jul. 11; 23(13):2361-6; Loakes and Brown, 5-Nitroindole as anuniversal base analogue. Nucleic Acids Res. 1994 Oct. 11;22(20):4039-43).

As used herein, “loop” refers to a structure formed by a single strandof a nucleic acid, in which complementary regions that flank aparticular single stranded nucleotide region hybridize in a way that thesingle stranded nucleotide region between the complementary regions isexcluded from duplex formation or Watson-Crick base pairing. A loop is asingle stranded nucleotide region of any length. Examples of loopsinclude the unpaired nucleotides present in such structures as hairpins,stem loops, or extended loops.

As used herein, “extended loop” in the context of a dsRNA refers to asingle stranded loop and in addition 1, 2, 3, 4, 5, 6 or up to 20 basepairs or duplexes flanking the loop. In an extended loop, nucleotidesthat flank the loop on the 5′ side form a duplex with nucleotides thatflank the loop on the 3′ side. An extended loop may form a hairpin orstem loop.

As used herein, “tetraloop” in the context of a dsRNA refers to a loop(a single stranded region) consisting of four nucleotides that forms astable secondary structure that contributes to the stability of adjacentWatson-Crick hybridized nucleotides. Without being limited to theory, atetraloop may stabilize an adjacent Watson-Crick base pair by stackinginteractions. In addition, interactions among the four nucleotides in atetraloop include but are not limited to non-Watson-Crick base pairing,stacking interactions, hydrogen bonding, and contact interactions(Cheong et al., Nature 1990 Aug. 16; 346(6285):680-2; Heus and Pardi,Science 1991 Jul. 12; 253(5016):191-4). A tetraloop confers an increasein the melting temperature (Tm) of an adjacent duplex that is higherthan expected from a simple model loop sequence consisting of fourrandom bases. For example, a tetraloop can confer a melting temperatureof at least 55° C. in 10 mM NaHPO₄ to a hairpin comprising a duplex ofat least 2 base pairs in length. A tetraloop may containribonucleotides, deoxyribonucleotides, modified nucleotides, andcombinations thereof. Examples of RNA tetraloops include the UNCG familyof tetraloops (e.g., UUCG), the GNRA family of tetraloops (e.g., GAAA),and the CUUG tetraloop. (Woese et al., Proc Natl Acad Sci USA. 1990November; 87(21):8467-71; Antao et al., Nucleic Acids Res. 1991 Nov. 11;19(21):5901-5). Examples of DNA tetraloops include the d(GNNA) family oftetraloops (e.g., d(GTTA), the d(GNRA)) family of tetraloops, thed(GNAB) family of tetraloops, the d(CNNG) family of tetraloops, thed(TNCG) family of tetraloops (e.g., d(TTCG)). (Nakano et al.Biochemistry, 41 (48), 14281-14292, 2002.; SHINJI et al. Nippon KagakkaiKoen Yokoshu VOL. 78th; NO. 2; PAGE. 731 (2000).)

As used herein, the term “siRNA” refers to a double stranded nucleicacid in which each strand comprises RNA, RNA analog(s) or RNA and DNA.The siRNA comprises between 19 and 23 nucleotides or comprises 21nucleotides. The siRNA typically has 2 bp overhangs on the 3′ ends ofeach strand such that the duplex region in the siRNA comprises 17-21nucleotides, or 19 nucleotides. Typically, the antisense strand of thesiRNA is sufficiently complementary with the target sequence of the α-1antitrypsin gene/RNA.

Where a first sequence is referred to as “substantially complementary”with respect to a second sequence herein, the two sequences can be fullycomplementary, or they may form one or more, but generally not more than4, 3 or 2 mismatched base pairs upon hybridization, while retaining theability to hybridize under the conditions most relevant to theirultimate application. However, where two oligonucleotides are designedto form, upon hybridization, one or more single stranded overhangs, suchoverhangs shall not be regarded as mismatches with regard to thedetermination of complementarity. For example, a dsRNA comprising oneoligonucleotide 21 nucleotides in length and another oligonucleotide 23nucleotides in length, wherein the longer oligonucleotide comprises asequence of 21 nucleotides that is fully complementary to the shorteroligonucleotide, may yet be referred to as “fully complementary” for thepurposes of the invention.

The term “double-stranded RNA” or “dsRNA”, as used herein, refers to acomplex of ribonucleic acid molecules, having a duplex structurecomprising two anti-parallel and substantially complementary, as definedabove, nucleic acid strands. The two strands forming the duplexstructure may be different portions of one larger RNA molecule, or theymay be separate RNA molecules. Where separate RNA molecules, such dsRNAare often referred to as siRNA (“short interfering RNA”) or DsiRNA(“Dicer substrate siRNAs”). Where the two strands are part of one largermolecule, and therefore are connected by an uninterrupted chain ofnucleotides between the 3′-end of one strand and the 5′ end of therespective other strand forming the duplex structure, the connecting RNAchain is referred to as a “hairpin loop”, “short hairpin RNA” or“shRNA”. Where the two strands are connected covalently by means otherthan an uninterrupted chain of nucleotides between the 3′-end of onestrand and the 5′end of the respective other strand forming the duplexstructure, the connecting structure is referred to as a “linker”. TheRNA strands may have the same or a different number of nucleotides. Themaximum number of base pairs is the number of nucleotides in theshortest strand of the dsRNA minus any overhangs that are present in theduplex. In addition to the duplex structure, a dsRNA may comprise one ormore nucleotide overhangs. In addition, as used herein, “dsRNA” mayinclude chemical modifications to ribonucleotides, internucleosidelinkages, end-groups, caps, and conjugated moieties, includingsubstantial modifications at multiple nucleotides and including alltypes of modifications disclosed herein or known in the art. Any suchmodifications, as used in an siRNA- or DsiRNA-type molecule, areencompassed by “dsRNA” for the purposes of this specification andclaims.

The phrase “duplex region” refers to the region in two complementary orsubstantially complementary oligonucleotides that form base pairs withone another, either by Watson-Crick base pairing or other manner thatallows for a duplex between oligonucleotide strands that arecomplementary or substantially complementary. For example, anoligonucleotide strand having 21 nucleotide units can base pair withanother oligonucleotide of 21 nucleotide units, yet only 19 bases oneach strand are complementary or substantially complementary, such thatthe “duplex region” consists of 19 base pairs. The remaining base pairsmay, for example, exist as 5′ and 3′ overhangs. Further, within theduplex region, 100% complementarity is not required; substantialcomplementarity is allowable within a duplex region. Substantialcomplementarity refers to complementarity between the strands such thatthey are capable of annealing under biological conditions. Techniques toempirically determine if two strands are capable of annealing underbiological conditions are well know in the art. Alternatively, twostrands can be synthesized and added together under biologicalconditions to determine if they anneal to one another.

By definition, “sufficiently complementary” (contrasted with, e.g.,“100% complementary”) allows for one or more mismatches to exist betweena dsRNA of the invention and the target RNA or cDNA sequence (e.g., α-1antitrypsin mRNA), provided that the dsRNA possesses complementaritysufficient to trigger the destruction of the target RNA by the RNAimachinery (e.g., the RISC complex) or process. In certain embodiments, a“sufficiently complementary” dsRNA of the invention can harbor one, two,three or even four or more mismatches between the dsRNA sequence and thetarget RNA or cDNA sequence (e.g., in certain such embodiments, theantisense strand of the dsRNA harbors one, two, three, four, five oreven six or more mismatches when aligned with the target RNA or cDNAsequence). Additional consideration of the preferred location of suchmismatches within certain dsRNAs of the instant invention is consideredin greater detail below.

As used herein “DsiRNAmm” refers to a DisRNA having a “mismatch tolerantregion” containing one, two, three or four mismatched base pairs of theduplex formed by the sense and antisense strands of the DsiRNA, wheresuch mismatches are positioned within the DsiRNA at a location(s) lyingbetween (and thus not including) the two terminal base pairs of eitherend of the DsiRNA. The structure and mismatch positioning of exemplaryforms of DsiRNAmm compositions are described in greater detail below.

Single-stranded nucleic acids that base pair over a number of bases aresaid to “hybridize.” Hybridization is typically determined underphysiological or biologically relevant conditions (e.g., intracellular:pH 7.2, 140 mM potassium ion; extracellular pH 7.4, 145 mM sodium ion).Hybridization conditions generally contain a monovalent cation andbiologically acceptable buffer and may or may not contain a divalentcation, complex anions, e.g. gluconate from potassium gluconate,uncharged species such as sucrose, and inert polymers to reduce theactivity of water in the sample, e.g. PEG. Such conditions includeconditions under which base pairs can form.

Hybridization is measured by the temperature required to dissociatesingle stranded nucleic acids forming a duplex, i.e., (the meltingtemperature; Tm). Hybridization conditions are also conditions underwhich base pairs can form. Various conditions of stringency can be usedto determine hybridization (see, e.g., Wahl, G. M. and S. L. Berger(1987) Methods Enzymol. 152:399; Kimmel, A. R. (1987) Methods Enzymol.152:507). Stringent temperature conditions will ordinarily includetemperatures of at least about 30° C., more preferably of at least about37° C., and most preferably of at least about 42° C. The hybridizationtemperature for hybrids anticipated to be less than 50 base pairs inlength should be 5-10° C. less than the melting temperature (Tm) of thehybrid, where Tm is determined according to the following equations. Forhybrids less than 18 base pairs in length, Tm(° C.)=2(# of A+Tbases)+4(# of G+C bases). For hybrids between 18 and 49 base pairs inlength, Tm(° C.)=81.5+16.6(log 10[Na+])+0.41 (% G+C)−(600/N), where N isthe number of bases in the hybrid, and [Na+] is the concentration ofsodium ions in the hybridization buffer ([Na+] for 1×SSC=0.165 M). Forexample, a hybridization determination buffer is shown in Table 1.

TABLE 1 To make 50 final conc. Vender Cat# Lot# m.w./Stock mL solutionNaCl  100 mM Sigma S-5150 41K8934 5M 1 mL KCl   80 mM Sigma P-954170K0002 74.55 0.298 g MgCl₂   8 mM Sigma M-1028 120K8933 1M 0.4 mLsucrose 2% w/v Fisher BP220-212 907105 342.3 1 g Tris-HCl   16 mM FisherBP1757-500 12419 1M 0.8 mL NaH₂PO₄    1 mM Sigma S-3193 52H-029515 120.00.006 g EDTA 0.02 mM Sigma E-7889 110K89271 0.5M 2 μL H₂O Sigma W-450251K2359 to 50 mL pH = 7.0 adjust with at 20° C. HCl

Useful variations on hybridization conditions will be readily apparentto those skilled in the art. Hybridization techniques are well known tothose skilled in the art and are described, for example, in Benton andDavis (Science 196:180, 1977); Grunstein and Hogness (Proc. Natl. Acad.Sci., USA 72:3961, 1975); Ausubel et al. (Current Protocols in MolecularBiology, Wiley Interscience, New York, 2001); Berger and Kimmel(Antisense to Molecular Cloning Techniques, 1987, Academic Press, NewYork); and Sambrook et al., Molecular Cloning: A Laboratory Manual, ColdSpring Harbor Laboratory Press, New York.

As used herein, “oligonucleotide strand” is a single stranded nucleicacid molecule. An oligonucleotide may comprise ribonucleotides,deoxyribonucleotides, modified nucleotides (e.g., nucleotides with 2′modifications, synthetic base analogs, etc.) or combinations thereof.Such modified oligonucleotides can be preferred over native formsbecause of properties such as, for example, enhanced cellular uptake andincreased stability in the presence of nucleases.

As used herein, the term “ribonucleotide” encompasses natural andsynthetic, unmodified and modified ribonucleotides. Modificationsinclude changes to the sugar moiety, to the base moiety and/or to thelinkages between ribonucleotides in the oligonucleotide. As used herein,the term “ribonucleotide” specifically excludes a deoxyribonucleotide,which is a nucleotide possessing a single proton group at the 2′ ribosering position.

As used herein, the term “deoxyribonucleotide” encompasses natural andsynthetic, unmodified and modified deoxyribonucleotides. Modificationsinclude changes to the sugar moiety, to the base moiety and/or to thelinkages between deoxyribonucleotide in the oligonucleotide. As usedherein, the term “deoxyribonucleotide” also includes a modifiedribonucleotide that does not permit Dicer cleavage of a dsRNA agent,e.g., a 2′-O-methyl ribonucleotide, a phosphorothioate-modifiedribonucleotide residue, etc., that does not permit Dicer cleavage tooccur at a bond of such a residue.

As used herein, the term “PS-NA” refers to a phosphorothioate-modifiednucleotide residue. The term “PS-NA” therefore encompasses bothphosphorothioate-modified ribonucleotides (“PS-RNAs”) andphosphorothioate-modified deoxyribonucleotides (“PS-DNAs”).

As used herein, “Dicer” refers to an endoribonuclease in the RNase IIIfamily that cleaves a dsRNA or dsRNA-containing molecule, e.g.,double-stranded RNA (dsRNA) or pre-microRNA (miRNA), intodouble-stranded nucleic acid fragments 19-25 nucleotides long, usuallywith a two-base overhang on the 3′ end. With respect to certain dsRNAsof the invention (e.g., “DsiRNAs”), the duplex formed by a dsRNA regionof an agent of the invention is recognized by Dicer and is a Dicersubstrate on at least one strand of the duplex. Dicer catalyzes thefirst step in the RNA interference pathway, which consequently resultsin the degradation of a target RNA. The protein sequence of human Diceris provided at the NCBI database under accession number NP_085124,hereby incorporated by reference.

Dicer “cleavage” can be determined as follows (e.g., see Collingwood etal., Oligonucleotides 18:187-200 (2008)). In a Dicer cleavage assay, RNAduplexes (100 pmol) are incubated in 20 μL of 20 mM Tris pH 8.0, 200 mMNaCl, 2.5 mM MgCl2 with or without 1 unit of recombinant human Dicer(Stratagene, La Jolla, Calif.) at 37° C. for 18-24 hours. Samples aredesalted using a Performa SR 96-well plate (Edge Biosystems,Gaithersburg, Md.). Electrospray-ionization liquid chromatography massspectroscopy (ESI-LCMS) of duplex RNAs pre- and post-treatment withDicer is done using an Oligo HTCS system (Novatia, Princeton, N.J.; Hailet al., 2004), which consists of a ThermoFinnigan TSQ7000, Xcalibur datasystem, ProMass data processing software and Paradigm MS4 HPLC (MichromBioResources, Auburn, Calif.). In this assay, Dicer cleavage occurswhere at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, oreven 100% of the Dicer substrate dsRNA, (i.e., 25-30 bp, dsRNA,preferably 26-30 bp dsRNA) is cleaved to a shorter dsRNA (e.g., 19-23 bpdsRNA, preferably, 21-23 bp dsRNA).

As used herein, “Dicer cleavage site” refers to the sites at which Dicercleaves a dsRNA (e.g., the dsRNA region of a DsiRNA agent of theinvention). Dicer contains two RNase III domains which typically cleaveboth the sense and antisense strands of a dsRNA. The average distancebetween the RNase III domains and the PAZ domain determines the lengthof the short double-stranded nucleic acid fragments it produces and thisdistance can vary (Macrae et al. (2006) Science 311: 195-8). As shown inFIG. 1 , Dicer is projected to cleave certain double-strandedribonucleic acids of the instant invention that possess an antisensestrand having a 2 nucleotide 3′ overhang at a site between the 21^(st)and 22^(nd) nucleotides removed from the 3′ terminus of the antisensestrand, and at a corresponding site between the 21^(st) and 22^(nd)nucleotides removed from the 5′ terminus of the sense strand. Theprojected and/or prevalent Dicer cleavage site(s) for dsRNA moleculesdistinct from those depicted in FIG. 1 may be similarly identified viaart-recognized methods, including those described in Macrae et al. Whilethe Dicer cleavage events depicted in FIG. 1 generate 21 nucleotidesiRNAs, it is noted that Dicer cleavage of a dsRNA (e.g., DsiRNA) canresult in generation of Dicer-processed siRNA lengths of 19 to 23nucleotides in length. Indeed, in certain embodiments, a double-strandedDNA region may be included within a dsRNA for purpose of directingprevalent Dicer excision of a typically non-preferred 19mer or 20mersiRNA, rather than a 21mer.

In certain embodiments, dsRNAs of the invention are Dicer substratesiRNAs (“DsiRNAs”). DsiRNAs can possess certain advantages as comparedto inhibitory nucleic acids that are not dicer substrates(“non-DsiRNAs”). Such advantages include, but are not limited to,enhanced duration of effect of a DsiRNA relative to a non-DsiRNA, aswell as enhanced inhibitory activity of a DsiRNA as compared to anon-DsiRNA (e.g., a 19-23mer siRNA) when each inhibitory nucleic acid issuitably formulated and assessed for inhibitory activity in a mammaliancell at the same concentration (in this latter scenario, the DsiRNAwould be identified as more potent than the non-DsiRNA). Detection ofthe enhanced potency of a DsiRNA relative to a non-DsiRNA is often mostreadily achieved at a formulated concentration (e.g., transfectionconcentration of the dsRNA) that results in the DsiRNA elicitingapproximately 30-70% knockdown activity upon a target RNA (e.g., amRNA). For active DsiRNAs, such levels of knockdown activity are mostoften achieved at in vitro mammalian cell DsiRNA transfectionconcentrations of 1 nM or less of as suitably formulated, and in certaininstances are observed at DsiRNA transfection concentrations of 200 pMor less, 100 pM or less, 50 pM or less, 20 pM or less, 10 pM or less, 5pM or less, or even 1 pM or less. Indeed, due to the variability amongDsiRNAs of the precise concentration at which 30-70% knockdown of atarget RNA is observed, construction of an IC₅₀ curve via assessment ofthe inhibitory activity of DsiRNAs and non-DsiRNAs across a range ofeffective concentrations is a preferred method for detecting theenhanced potency of a DsiRNA relative to a non-DsiRNA inhibitory agent.

As used herein, “overhang” refers to unpaired nucleotides, in thecontext of a duplex having one or more free ends at the 5′ terminus or3′ terminus of a dsRNA. In certain embodiments, the overhang is a 3′ or5′ overhang on the antisense strand or sense strand. In someembodiments, the overhang is a 3′ overhang having a length of betweenone and six nucleotides, optionally one to five, one to four, one tothree, one to two, two to six, two to five, two to four, two to three,three to six, three to five, three to four, four to six, four to five,five to six nucleotides, or one, two, three, four, five or sixnucleotides. “Blunt” or “blunt end” means that there are no unpairednucleotides at that end of the dsRNA, i.e., no nucleotide overhang. Forclarity, chemical caps or non-nucleotide chemical moieties conjugated tothe 3′ end or 5′ end of an siRNA are not considered in determiningwhether an siRNA has an overhang or is blunt ended. In certainembodiments, the invention provides a dsRNA molecule for inhibiting theexpression of the α-1 antitrypsin target gene in a cell or mammal,wherein the dsRNA comprises an antisense strand comprising a region ofcomplementarity which is complementary to at least a part of an mRNAformed in the expression of the α-1 antitrypsin target gene, and whereinthe region of complementarity is less than 35 nucleotides in length,optionally 19-24 nucleotides in length or 25-30 nucleotides in length,and wherein the dsRNA, upon contact with a cell expressing the α-1antitrypsin target gene, inhibits the expression of the α-1 antitrypsintarget gene by at least 10%, 25%, or 40%.

As used herein, the term “RNA processing” refers to processingactivities performed by components of the siRNA, miRNA or RNase Hpathways (e.g., Drosha, Dicer, Argonaute2 or other RISCendoribonucleases, and RNaseH), which are described in greater detailbelow (see “RNA Processing” section below). The term is explicitlydistinguished from the post-transcriptional processes of 5′ capping ofRNA and degradation of RNA via non-RISC- or non-RNase H-mediatedprocesses. Such “degradation” of an RNA can take several forms, e.g.deadenylation (removal of a 3′ poly(A) tail), and/or nuclease digestionof part or all of the body of the RNA by one or more of several endo- orexo-nucleases (e.g., RNase III, RNase P, RNase T1, RNase A (1, 2, 3,4/5), oligonucleotidase, etc.).

By “homologous sequence” is meant a nucleotide sequence that is sharedby one or more polynucleotide sequences, such as genes, gene transcriptsand/or non-coding polynucleotides. For example, a homologous sequencecan be a nucleotide sequence that is shared by two or more genesencoding related but different proteins, such as different members of agene family, different protein epitopes, different protein isoforms orcompletely divergent genes, such as a cytokine and its correspondingreceptors. A homologous sequence can be a nucleotide sequence that isshared by two or more non-coding polynucleotides, such as noncoding DNAor RNA, regulatory sequences, introns, and sites of transcriptionalcontrol or regulation. Homologous sequences can also include conservedsequence regions shared by more than one polynucleotide sequence.Homology does not need to be perfect homology (e.g., 100%), as partiallyhomologous sequences are also contemplated by the instant invention(e.g., 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%,86%, 85%, 84%, 83%, 82%, 81%, 80% etc.). Indeed, design and use of thedsRNA agents of the instant invention contemplates the possibility ofusing such dsRNA agents not only against target RNAs of α-1 antitrypsinpossessing perfect complementarity with the presently described dsRNAagents, but also against target α-1 antitrypsin RNAs possessingsequences that are, e.g., only 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%,91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80% etc.complementary to said dsRNA agents. Similarly, it is contemplated thatthe presently described dsRNA agents of the instant invention might bereadily altered by the skilled artisan to enhance the extent ofcomplementarity between said dsRNA agents and a target α-1 antitrypsinRNA, e.g., of a specific allelic variant of α-1 antitrypsin (e.g., anallele of enhanced therapeutic interest). Indeed, dsRNA agent sequenceswith insertions, deletions, and single point mutations relative to thetarget α-1 antitrypsin sequence can also be effective for inhibition.Alternatively, dsRNA agent sequences with nucleotide analogsubstitutions or insertions can be effective for inhibition.

Sequence identity may be determined by sequence comparison and alignmentalgorithms known in the art. To determine the percent identity of twonucleic acid sequences (or of two amino acid sequences), the sequencesare aligned for comparison purposes (e.g., gaps can be introduced in thefirst sequence or second sequence for optimal alignment). Thenucleotides (or amino acid residues) at corresponding nucleotide (oramino acid) positions are then compared. When a position in the firstsequence is occupied by the same residue as the corresponding positionin the second sequence, then the molecules are identical at thatposition. The percent identity between the two sequences is a functionof the number of identical positions shared by the sequences (i.e., %homology=# of identical positions/total # of positions×100), optionallypenalizing the score for the number of gaps introduced and/or length ofgaps introduced.

The comparison of sequences and determination of percent identitybetween two sequences can be accomplished using a mathematicalalgorithm. In one embodiment, the alignment generated over a certainportion of the sequence aligned having sufficient identity but not overportions having low degree of identity (i.e., a local alignment). Apreferred, non-limiting example of a local alignment algorithm utilizedfor the comparison of sequences is the algorithm of Karlin and Altschul(1990) Proc. Natl. Acad. Sci. USA 87:2264-68, modified as in Karlin andAltschul (1993) Proc. Natl. Acad. Sci. USA 90:5873-77. Such an algorithmis incorporated into the BLAST programs (version 2.0) of Altschul, etal. (1990) J. Mol. Biol. 215:403-10.

In another embodiment, a gapped alignment, the alignment is optimized byintroducing appropriate gaps, and percent identity is determined overthe length of the aligned sequences (i.e., a gapped alignment). Toobtain gapped alignments for comparison purposes, Gapped BLAST can beutilized as described in Altschul et al., (1997) Nucleic Acids Res.25(17):3389-3402. In another embodiment, a global alignment thealignment is optimized by introducing appropriate gaps, and percentidentity is determined over the entire length of the sequences aligned.(i.e., a global alignment). A preferred, non-limiting example of amathematical algorithm utilized for the global comparison of sequencesis the algorithm of Myers and Miller, CABIOS (1989). Such an algorithmis incorporated into the ALIGN program (version 2.0) which is part ofthe GCG sequence alignment software package. When utilizing the ALIGNprogram for comparing amino acid sequences, a PAM120 weight residuetable, a gap length penalty of 12, and a gap penalty of 4 can be used.

Greater than 80% sequence identity, e.g., 80%, 81%, 82%, 83%, 84%, 85%,86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% oreven 100% sequence identity, between the dsRNA antisense strand and theportion of the α-1 antitrypsin RNA sequence is preferred. Alternatively,the dsRNA may be defined functionally as a nucleotide sequence (oroligonucleotide sequence) that is capable of hybridizing with a portionof the α-1 antitrypsin RNA (e.g., 400 mM NaCl, 40 mM PIPES pH 6.4, 1 mMEDTA, 50° C. or 70° C. hybridization for 12-16 hours; followed bywashing). Additional preferred hybridization conditions includehybridization at 70° C. in 1×SSC or 50° C. in 1×SSC, 50% formamidefollowed by washing at 70° C. in 0.3×SSC or hybridization at 70° C. in4×SSC or 50° C. in 4×SSC, 50% formamide followed by washing at 67° C. in1×SSC. The hybridization temperature for hybrids anticipated to be lessthan 50 base pairs in length should be 5-10° C. less than the meltingtemperature (Tm) of the hybrid, where Tm is determined according to thefollowing equations. For hybrids less than 18 base pairs in length, Tm(°C.)=2(# of A+T bases)+4(# of G+C bases). For hybrids between 18 and 49base pairs in length, Tm(° C.)=81.5+16.6(log 10[Na+])+0.41 (%G+C)−(600/N), where N is the number of bases in the hybrid, and [Na+] isthe concentration of sodium ions in the hybridization buffer ([Na+] for1×SSC=0.165 M). Additional examples of stringency conditions forpolynucleotide hybridization are provided in Sambrook, J., E. F.Fritsch, and T. Maniatis, 1989, Molecular Cloning: A Laboratory Manual,Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., chapters9 and 11, and Current Protocols in Molecular Biology, 1995, F. M.Ausubel et al., eds., John Wiley & Sons, Inc., sections 2.10 and6.3-6.4. The length of the identical nucleotide sequences may be atleast 10, 12, 15, 17, 20, 22, 25, 27 or 30 bases.

By “conserved sequence region” is meant, a nucleotide sequence of one ormore regions in a polynucleotide does not vary significantly betweengenerations or from one biological system, subject, or organism toanother biological system, subject, or organism. The polynucleotide caninclude both coding and non-coding DNA and RNA.

By “sense region” is meant a nucleotide sequence of a dsRNA moleculehaving complementarity to an antisense region of the dsRNA molecule. Inaddition, the sense region of a dsRNA molecule can comprise a nucleicacid sequence having homology with a target nucleic acid sequence.

By “antisense region” is meant a nucleotide sequence of a dsRNA moleculehaving complementarity to a target nucleic acid sequence. In addition,the antisense region of a dsRNA molecule comprises a nucleic acidsequence having complementarity to a sense region of the dsRNA molecule.

As used herein, “antisense strand” refers to a single stranded nucleicacid molecule which has a sequence complementary to that of a targetRNA. When the antisense strand contains modified nucleotides with baseanalogs, it is not necessarily complementary over its entire length, butmust at least hybridize with a target RNA.

As used herein, “sense strand” refers to a single stranded nucleic acidmolecule which has a sequence complementary to that of an antisensestrand. When the antisense strand contains modified nucleotides withbase analogs, the sense strand need not be complementary over the entirelength of the antisense strand, but must at least duplex with theantisense strand.

As used herein, “guide strand” refers to a single stranded nucleic acidmolecule of a dsRNA or dsRNA-containing molecule, which has a sequencesufficiently complementary to that of a target RNA to result in RNAinterference. After cleavage of the dsRNA or dsRNA-containing moleculeby Dicer, a fragment of the guide strand remains associated with RISC,binds a target RNA as a component of the RISC complex, and promotescleavage of a target RNA by RISC. As used herein, the guide strand doesnot necessarily refer to a continuous single stranded nucleic acid andmay comprise a discontinuity, preferably at a site that is cleaved byDicer. A guide strand is an antisense strand.

As used herein, “passenger strand” refers to an oligonucleotide strandof a dsRNA or dsRNA-containing molecule, which has a sequence that iscomplementary to that of the guide strand. As used herein, the passengerstrand does not necessarily refer to a continuous single strandednucleic acid and may comprise a discontinuity, preferably at a site thatis cleaved by Dicer. A passenger strand is a sense strand.

By “target nucleic acid” is meant a nucleic acid sequence whoseexpression, level or activity is to be modulated. The target nucleicacid can be DNA or RNA. For agents that target α-1 antitrypsin, incertain embodiments, the target nucleic acid is α-1 antitrypsin RNA,e.g., in certain embodiments, α-1 antitrypsin mRNA. α-1 antitrypsin RNAtarget sites can also interchangeably be referenced by correspondingcDNA sequences. Levels of α-1 antitrypsin may also be targeted viatargeting of upstream effectors of α-1 antitrypsin, or the effects ofmodulated or misregulated α-1 antitrypsin may also be modulated bytargeting of molecules downstream of α-1 antitrypsin in the α-1antitrypsin signalling pathway.

By “complementarity” is meant that a nucleic acid can form hydrogenbond(s) with another nucleic acid sequence by either traditionalWatson-Crick or other non-traditional types. In reference to the nucleicmolecules of the present invention, the binding free energy for anucleic acid molecule with its complementary sequence is sufficient toallow the relevant function of the nucleic acid to proceed, e.g., RNAiactivity. Determination of binding free energies for nucleic acidmolecules is well known in the art (see, e.g., Turner et al., 1987, CSHSymp. Quant. Biol. LII pp. 123-133; Frier et al., 1986, Proc. Nat. Acad.Sci. USA 83:9373-9377; Turner et al., 1987, J. Am. Chem. Soc.109:3783-3785). A percent complementarity indicates the percentage ofcontiguous residues in a nucleic acid molecule that can form hydrogenbonds (e.g., Watson-Crick base pairing) with a second nucleic acidsequence (e.g., 5, 6, 7, 8, 9, or 10 nucleotides out of a total of 10nucleotides in the first oligonucleotide being based paired to a secondnucleic acid sequence having 10 nucleotides represents 50%, 60%, 70%,80%, 90%, and 100% complementary respectively). “Perfectlycomplementary” means that all the contiguous residues of a nucleic acidsequence will hydrogen bond with the same number of contiguous residuesin a second nucleic acid sequence. In one embodiment, a dsRNA moleculeof the invention comprises 19 to 30 (e.g., 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, or 30 or more) nucleotides that are complementary to oneor more target nucleic acid molecules or a portion thereof.

As used herein, a dsRNA, e.g., DsiRNA or siRNA, having a sequence“sufficiently complementary” to a target RNA or cDNA sequence (e.g., α-1antitrypsin mRNA) means that the dsRNA has a sequence sufficient totrigger the destruction of the target RNA (where a cDNA sequence isrecited, the RNA sequence corresponding to the recited cDNA sequence) bythe RNAi machinery (e.g., the RISC complex) or process. For example, adsRNA that is “sufficiently complementary” to a target RNA or cDNAsequence to trigger the destruction of the target RNA by the RNAimachinery or process can be identified as a dsRNA that causes adetectable reduction in the level of the target RNA in an appropriateassay of dsRNA activity (e.g., an in vitro assay as described in Example2 below), or, in further examples, a dsRNA that is sufficientlycomplementary to a target RNA or cDNA sequence to trigger thedestruction of the target RNA by the RNAi machinery or process can beidentified as a dsRNA that produces at least a 5%, at least a 10%, atleast a 15%, at least a 20%, at least a 25%, at least a 30%, at least a35%, at least a 40%, at least a 45%, at least a 50%, at least a 55%, atleast a 60%, at least a 65%, at least a 70%, at least a 75%, at least a80%, at least a 85%, at least a 90%, at least a 95%, at least a 98% orat least a 99% reduction in the level of the target RNA in anappropriate assay of dsRNA activity. In additional examples, a dsRNAthat is sufficiently complementary to a target RNA or cDNA sequence totrigger the destruction of the target RNA by the RNAi machinery orprocess can be identified based upon assessment of the duration of acertain level of inhibitory activity with respect to the target RNA orprotein levels in a cell or organism. For example, a dsRNA that issufficiently complementary to a target RNA or cDNA sequence to triggerthe destruction of the target RNA by the RNAi machinery or process canbe identified as a dsRNA capable of reducing target mRNA levels by atleast 20% at least 48 hours post-administration of said dsRNA to a cellor organism. Preferably, a dsRNA that is sufficiently complementary to atarget RNA or cDNA sequence to trigger the destruction of the target RNAby the RNAi machinery or process is identified as a dsRNA capable ofreducing target mRNA levels by at least 40% at least 72 hourspost-administration of said dsRNA to a cell or organism, by at least 40%at least four, five or seven days post-administration of said dsRNA to acell or organism, by at least 50% at least 48 hours post-administrationof said dsRNA to a cell or organism, by at least 50% at least 72 hourspost-administration of said dsRNA to a cell or organism, by at least 50%at least four, five or seven days post-administration of said dsRNA to acell or organism, by at least 80% at least 48 hours post-administrationof said dsRNA to a cell or organism, by at least 80% at least 72 hourspost-administration of said dsRNA to a cell or organism, or by at least80% at least four, five or seven days post-administration of said dsRNAto a cell or organism.

In certain embodiments, a nucleic acid of the invention (e.g., a DsiRNAor siRNA) possesses a sequence “sufficiently complementary to hybridize”to a target RNA or cDNA sequence, thereby achieving an inhibitory effectupon the target RNA. Hybridization, and conditions available fordetermining whether one nucleic acid is sufficiently complementary toanother nucleic acid to allow the two sequences to hybridize, isdescribed in greater detail below.

As used herein “cell” is used in its usual biological sense, and doesnot refer to an entire multicellular organism, e.g., specifically doesnot refer to a human. The cell can be present in an organism, e.g.,birds, plants and mammals such as humans, cows, sheep, apes, monkeys,swine, dogs, and cats. The cell can be prokaryotic (e.g., bacterialcell) or eukaryotic (e.g., mammalian or plant cell). The cell can be ofsomatic or germ line origin, totipotent or pluripotent, dividing ornon-dividing. The cell can also be derived from or can comprise a gameteor embryo, a stem cell, or a fully differentiated cell. Within certainaspects, the term “cell” refers specifically to mammalian cells, such ashuman cells, that contain one or more dsRNA molecules of the presentdisclosure. In particular aspects, a cell processes dsRNAs ordsRNA-containing molecules resulting in RNA interference of targetnucleic acids, and contains proteins and protein complexes required forRNAi, e.g., Dicer and RISC.

By “RNA” is meant a molecule comprising at least one, and preferably atleast 4, 8 and 12 ribonucleotide residues. The at least 4, 8 or 12 RNAresidues may be contiguous. By “ribonucleotide” is meant a nucleotidewith a hydroxyl group at the 2′ position of a β-D-ribofuranose moiety.The terms include double-stranded RNA, single-stranded RNA, RNA such aspartially purified RNA, essentially pure RNA, synthetic RNA,recombinantly produced RNA, as well as altered RNA that differs fromnaturally occurring RNA by the addition, deletion, substitution and/oralteration of one or more nucleotides. Such alterations can includeaddition of non-nucleotide material, such as to the end(s) of the dsRNAor internally, for example at one or more nucleotides of the RNA.Nucleotides in the RNA molecules of the instant invention can alsocomprise non-standard nucleotides, such as non-naturally occurringnucleotides or chemically synthesized nucleotides or deoxynucleotides.These altered RNAs can be referred to as analogs or analogs ofnaturally-occurring RNA.

In certain embodiments, an RNAi agent (e.g., dsRNA) of the invention canbe an “isolated” RNAi agent, meaning that the RNAi agent is isolatedfrom (removed and/or purified from) a natural environment.

In some embodiments, an RNAi agent (e.g., dsRNA) of the invention can bea “synthetic” RNAi agent. The term “synthetic” or “non-natural” refersto an RNAi agent (e.g., a dsRNA of the disclosure) that (i) issynthesized using a machine or (ii) that is not derived from a cell ororganism that normally produces the RNAi agent.

By “subject” is meant an organism, which is a donor or recipient ofexplanted cells or the cells themselves. “Subject” also refers to anorganism to which the dsRNA agents of the invention can be administered.A subject can be a mammal or mammalian cells, including a human or humancells.

The phrase “pharmaceutically acceptable carrier” refers to a carrier forthe administration of a therapeutic agent. Exemplary carriers includesaline, buffered saline, dextrose, water, glycerol, ethanol, andcombinations thereof. For drugs administered orally, pharmaceuticallyacceptable carriers include, but are not limited to pharmaceuticallyacceptable excipients such as inert diluents, disintegrating agents,binding agents, lubricating agents, sweetening agents, flavoring agents,coloring agents and preservatives. Suitable inert diluents includesodium and calcium carbonate, sodium and calcium phosphate, and lactose,while corn starch and alginic acid are suitable disintegrating agents.Binding agents may include starch and gelatin, while the lubricatingagent, if present, will generally be magnesium stearate, stearic acid ortalc. If desired, the tablets may be coated with a material such asglyceryl monostearate or glyceryl distearate, to delay absorption in thegastrointestinal tract. The pharmaceutically acceptable carrier of thedisclosed dsRNA compositions may be micellar structures, such as aliposomes, capsids, capsoids, polymeric nanocapsules, or polymericmicrocapsules.

Polymeric nanocapsules or microcapsules facilitate transport and releaseof the encapsulated or bound dsRNA into the cell. They include polymericand monomeric materials, especially including polybutylcyanoacrylate. Asummary of materials and fabrication methods has been published (seeKreuter, 1991). The polymeric materials which are formed from monomericand/or oligomeric precursors in the polymerization/nanoparticlegeneration step, are per se known from the prior art, as are themolecular weights and molecular weight distribution of the polymericmaterial which a person skilled in the field of manufacturingnanoparticles may suitably select in accordance with the usual skill.

The term “in vitro” has its art recognized meaning, e.g., involvingpurified reagents or extracts, e.g., cell extracts. The term “in vivo”also has its art recognized meaning, e.g., involving living cells, e.g.,immortalized cells, primary cells, cell lines, and/or cells in anorganism.

“Treatment”, or “treating” as used herein, is defined as the applicationor administration of a therapeutic agent (e.g., a dsRNA agent or avector or transgene encoding same) to a patient, or application oradministration of a therapeutic agent to an isolated tissue or cell linefrom a patient, who has a disorder with the purpose to cure, heal,alleviate, relieve, alter, remedy, ameliorate, improve or affect thedisease or disorder, or symptoms of the disease or disorder. The term“treatment” or “treating” is also used herein in the context ofadministering agents prophylactically. The term “effective dose” or“effective dosage” is defined as an amount sufficient to achieve or atleast partially achieve the desired effect. The term “therapeuticallyeffective dose” is defined as an amount sufficient to cure or at leastpartially arrest the disease and its complications in a patient alreadysuffering from the disease. The term “patient” includes human and othermammalian subjects that receive either prophylactic or therapeutictreatment.

Various methodologies of the instant invention include at least one stepthat involves comparing a value, level, feature, characteristic,property, etc. to a “suitable control”, referred to interchangeablyherein as an “appropriate control”. A “suitable control” or “appropriatecontrol” is a control or standard familiar to one of ordinary skill inthe art useful for comparison purposes. In one embodiment, a “suitablecontrol” or “appropriate control” is a value, level, feature,characteristic, property, etc. determined prior to performing an RNAimethodology, as described herein. For example, a transcription rate,mRNA level, translation rate, protein level, biological activity,cellular characteristic or property, genotype, phenotype, etc. can bedetermined prior to introducing an RNA silencing agent (e.g., DsiRNA) ofthe invention into a cell or organism. In another embodiment, a“suitable control” or “appropriate control” is a value, level, feature,characteristic, property, etc. determined in a cell or organism, e.g., acontrol or normal cell or organism, exhibiting, for example, normaltraits. In yet another embodiment, a “suitable control” or “appropriatecontrol” is a predefined value, level, feature, characteristic,property, etc.

α-1 Antitrypsin as an RNAi Target

Alpha 1-antitrypsin (AAT or Serpina1) is a protease inhibitor belongingto the serpin superfamily. It is generally known as serum trypsininhibitor. Alpha 1-antitrypsin is also referred to as alpha-1 proteinaseinhibitor (A1PI) because it inhibits a wide variety of proteases(Gettins PG. Chem Rev 102: 4751-804). It protects tissues from enzymesof inflammatory cells, especially neutrophil elastase, and has areference range in blood of 1.5-3.5 gram/liter, but multi-fold elevatedlevels can occur upon acute inflammation (Kushner, Mackiewicz.Acute-phase glycoproteins: molecular biology, biochemistry and clinicalapplications (CRC Press). pp. 3-19). In the absence of AAT, neutrophilelastase is free to break down elastin, which contributes to theelasticity of the lungs, resulting in respiratory complications such asemphysema, or COPD (chronic obstructive pulmonary disease) in adults andcirrhosis in adults or children. Individuals with mutations in one orboth copies of the AAT gene can suffer from alpha-1 anti-trypsindeficiency, which presents as a risk of developing pulmonary emphysemaor chronic liver disease due to greater than normal elastase activity inthe lungs and liver.

As mentioned above, in certain disease states associated with α-1antitrypsin expression, an individual is producing significantquantities of alpha-1 antitrypsin, but a significant proportion of theα-1 antitrypsin protein being produced is misfolded or containsmutations that compromise the functioning of the protein. In certainsuch cases, the individual is producing misfolded proteins which cannotbe properly transported from the site of synthesis to the site of actionwithin the body.

Liver disease resulting from α-1 antitrypsin deficiency can be caused bysuch misfolded proteins. Mutant forms of α-1 antitrypsin (e.g., thecommon PiZ variant, which harbors a glutamate to lysine mutation atposition 342 (position 366 in pre-processed form)) are produced in livercells (hepatocytes in the liver commonly produce a large amount ofcirculating AAT), and in the misfolded configuration, such forms are notreadily transported out of the cells. This leads to a buildup ofmisfolded protein in the liver cells and can cause one or more diseasesor disorders of the liver including, but not limited to, chronic liverdisease, liver inflammation, cirrhosis, liver fibrosis, and/orhepatocellular carcinoma.

RNAi therapies are newly identified to provide an attractive, targetedmeans of treating the effects of mutant forms of α-1 antitrypsin at amolecular level. Notably, RNAi therapies, such as the dsRNAs that arespecifically exemplified herein, have demonstrated particularly goodability to be delivered to the cells of the liver in vivo (via, e.g.,lipid nanoparticles and/or conjugates such as dynamic polyconjugates orGalNAc conjugates). Thus, formulated RNAi therapies, such as thosedescribed herein, are attractive modalities for treating or preventingdiseases or disorders (especially the liver-specific diseases ordisorders, e.g., chronic liver disease, liver inflammation, cirrhosis,liver fibrosis, and/or hepatocellular carcinoma) associated with mutantforms of α-1 antitrypsin.

Use of RNAi therapies to target α-1 antitrypsin at a molecular level inother tissues is also contemplated. Most notably, in the lung, thepresence of mutant, inactive forms of α-1 antitrypsin in the serum cancause a deficiency in serum levels of active α-1 antitrypsin, resultingin host tissues that are susceptible to damage by neutrophil proteases.As a result, such lung tissues are rendered especially at risk ofsmoking injury, and lung-directed RNAi therapeutics such as thosedescribed herein offer an attractive and precise therapy.

α-1 Antitrypsin cDNA and Polypeptide Sequences

Known human and mouse α-1 antitrypsin cDNA and polypeptide sequencesinclude the following: human α-1 antitrypsin NM_000295.4 andcorresponding human α-1 antitrypsin polypeptide sequence GenBankAccession No. NP_000286.3; and mouse wild-type α-1 antitrypsin sequenceGenBank Accession No. NM_009246.3 (Mus musculus C57BL/6 Serpina1d) andcorresponding mouse Serpina1d sequence GenBank Accession No.NP_033272.1.

Assessment of α-1 Antitrypsin Levels

In certain embodiments, dsRNA-mediated inhibition of a α-1 antitrypsintarget sequence is assessed. In such embodiments, α-1 antitrypsin RNAlevels can be assessed by art-recognized methods (e.g., RT-PCR, Northernblot, expression array, etc.), optionally via comparison of α-1antitrypsin levels in the presence of an anti-α-1 antitrypsin dsRNA ofthe invention relative to the absence of such an anti-α-1 antitrypsindsRNA. In certain embodiments, α-1 antitrypsin levels in the presence ofan anti-α-1 antitrypsin dsRNA are compared to those observed in thepresence of vehicle alone, in the presence of a dsRNA directed againstan unrelated target RNA, or in the absence of any treatment.

It is also recognized that levels of α-1 antitrypsin protein can beassessed and that α-1 antitrypsin protein levels are, under differentconditions, either directly or indirectly related to α-1 antitrypsin RNAlevels and/or the extent to which a dsRNA inhibits α-1 antitrypsinexpression, thus art-recognized methods of assessing α-1 antitrypsinprotein levels (e.g., Western blot, immunoprecipitation, otherantibody-based methods, etc.) can also be employed to examine theinhibitory effect of a dsRNA of the invention.

In certain embodiments, potency of a dsRNA of the invention isdetermined in reference to the number of copies of a dsRNA present inthe cytoplasm of a target cell that are required to achieve a certainlevel of target gene knockdown. For example, in certain embodiments, apotent dsRNA is one capable of causing 50% or greater knockdown of atarget mRNA when present in the cytoplasm of a target cell at a copynumber of 1000 or fewer RISC-loaded antisense strands per cell. Morepreferably, a potent dsRNA is one capable of producing 50% or greaterknockdown of a target mRNA when present in the cytoplasm of a targetcell at a copy number of 500 or fewer RISC-loaded antisense strands percell. Optionally, a potent dsRNA is one capable of producing 50% orgreater knockdown of a target mRNA when present in the cytoplasm of atarget cell at a copy number of 300 or fewer RISC-loaded antisensestrands per cell.

In further embodiments, the potency of a DsiRNA of the invention can bedefined in reference to a 19 to 23mer dsRNA directed to the same targetsequence within the same target gene. For example, a DsiRNA of theinvention that possesses enhanced potency relative to a corresponding 19to 23mer dsRNA can be a DsiRNA that reduces a target gene by anadditional 5% or more, an additional 10% or more, an additional 20% ormore, an additional 30% or more, an additional 40% or more, or anadditional 50% or more as compared to a corresponding 19 to 23mer dsRNA,when assayed in an in vitro assay as described herein at a sufficientlylow concentration to allow for detection of a potency difference (e.g.,transfection concentrations at or below 1 nM in the environment of acell, at or below 100 pM in the environment of a cell, at or below 10 pMin the environment of a cell, at or below 1 nM in the environment of acell, in an in vitro assay as described herein; notably, it isrecognized that potency differences can be best detected via performanceof such assays across a range of concentrations—e.g., 0.1 pM to 10nM—for purpose of generating a dose-response curve and identifying anIC₅₀ value associated with a DsiRNA/dsRNA).

In certain embodiments, a nucleic acid of the invention is administeredin an amount sufficient to reduce α-1 antitrypsin target mRNA expressionwhen the nucleic acid is introduced into a mammalian cell. In exemplaryembodiments, reduction of α-1 antitrypsin target mRNA expression isassessed to have occurred if α-1 antitrypsin target mRNA levels aredecreased by at least 5% or more, 10% or more, 20% or more, 30% or more,40% or more, 50% or more, 60% or more, 70% or more, 80% or more, or 90%or more, as compared to a corresponding mammalian cell administered anappropriate control that does not include the α-1 antitrypsin-targetingnucleic acid of the invention. In an exemplary embodiment, the mammaliancell used to determine whether reduction of α-1 antitrypsin target mRNAexpression has occurred relative to an appropriate control is a Huh7cell, and the α-1 antitrypsin-targeting nucleic acid of the invention isoptionally administered via transfection (e.g., using Lipofectamine™) ata concentration of at or below 1 nM in the environment of a cell, at orbelow 100 pM in the environment of a cell, at or below 10 pM in theenvironment of a cell, at or below 1 nM in the environment of a cell, inan in vitro assay as described herein.

α-1 antitrypsin inhibitory levels and/or α-1 antitrypsin levels may alsobe assessed indirectly, e.g., measurement of a reduction of the size,number and/or rate of growth or spread of polyps or tumors in a subjectmay be used to assess α-1 antitrypsin levels and/or α-1 antitrypsininhibitory efficacy of a double-stranded nucleic acid of the instantinvention.

Models Useful to Evaluate the Down-Regulation of α-1 Antitrypsin mRNALevels and Expression

Therapeutic agents can be tested in selected animal model(s). Forexample, a dsRNA agent (or expression vector or transgene encoding same)as described herein can be used in an animal model to determine theefficacy, toxicity, or side effects of treatment with said agent.Alternatively, an agent (e.g., a therapeutic agent) can be used in ananimal model to determine the mechanism of action of such an agent.

Cell Culture

The dsRNA agents of the invention can be tested for cleavage activity invivo, for example, using the following procedure. The nucleotidesequences within the α-1 antitrypsin cDNA targeted by the dsRNA agentsof the invention are shown in the above α-1 antitrypsin sequences.

The dsRNA reagents of the invention can be tested in cell culture usingHuh7 or other mammalian cells (e.g., human cell lines Hep3B, HepG2,DU145, Calu3, SW480, T84, PL45, HeLa etc., and mouse cell lines AML12,Neuro2a, etc.) to determine the extent of α-1 antitrypsin RNA and α-1antitrypsin protein inhibition. In certain embodiments, DsiRNA reagents(e.g., see FIG. 1 , and exemplary structures recited elsewhere herein)are selected against the α-1 antitrypsin target as described herein. α-1antitrypsin RNA inhibition is measured after delivery of these reagentsby a suitable transfection agent to, for example, cultured Huh7 cells orother transformed or non-transformed mammalian cells in culture.Relative amounts of target α-1 antitrypsin RNA are measured versusHPRT1, actin or other appropriate control using real-time PCR monitoringof amplification (e.g., ABI 7700 TAQMAN®). A comparison is made to theactivity of oligonucleotide sequences made to unrelated targets or to arandomized DsiRNA control with the same overall length and chemistry, orsimply to appropriate vehicle-treated or untreated controls. Primary andsecondary lead reagents are chosen for the target and optimizationperformed.

TAQMAN® (Real-Time PCR Monitoring of Amplification) and LightcyclerQuantification of mRNA

Total RNA is prepared from cells following DsiRNA delivery, for example,using Ambion Rnaqueous 4-PCR purification kit for large scaleextractions, or Promega SV96 for 96-well assays. For Taqman analysis,dual-labeled probes are synthesized with, for example, the reporter dyesFAM or VIC covalently linked at the 5′-end and the quencher dye TAMRAconjugated to the 3′-end. PCR amplifications are performed on, forexample, an ABI PRISM 7700 Sequence detector using 50 uL reactionsconsisting of 10 uL total RNA, 100 nM forward primer, 100 mM reverseprimer, 100 nM probe, 1×TaqMan PCR reaction buffer (PE-AppliedBiosystems), 5.5 mM MgCl2, 100 uM each dATP, dCTP, dGTP and dTTP, 0.2URNase Inhibitor (Promega), 0.025U AmpliTaq Gold (PE-Applied Biosystems)and 0.2U M-MLV Reverse Transcriptase (Promega). The thermal cyclingconditions can consist of 30 minutes at 48° C., 10 minutes at 95° C.,followed by 40 cycles of 15 seconds at 95° C. and 1 minute at 60° C.Quantitation of target α-1 antitrypsin mRNA level is determined relativeto standards generated from serially diluted total cellular RNA (300,100, 30, 10 ng/rxn) and normalizing to, for example, HPRT1 mRNA ineither parallel or same tube TaqMan reactions.

Western Blotting

Cellular protein extracts can be prepared using a standard micropreparation technique (for example using RIPA buffer), or preferably, byextracting nuclear proteins by a method such as the NE-PER Nuclear andCytoplasmic Extraction kit (Thermo-Fisher Scientific). Cellular proteinextracts are run on Tris-Glycine polyacrylamide gel and transferred ontomembranes. Non-specific binding can be blocked by incubation, forexample, with 5% non-fat milk for 1 hour followed by primary antibodyfor 16 hours at 4° C. Following washes, the secondary antibody isapplied, for example (1:10,000 dilution) for 1 hour at room temperatureand the signal detected on a VersaDoc imaging system

In several cell culture systems, cationic lipids have been shown toenhance the bioavailability of oligonucleotides to cells in culture(Bennet, et al., 1992, Mol. Pharmacology, 41, 1023-1033). In oneembodiment, dsRNA molecules of the invention are complexed with cationiclipids for cell culture experiments. dsRNA and cationic lipid mixturesare prepared in serum-free OptimMEM (InVitrogen) immediately prior toaddition to the cells. OptiMEM is warmed to room temperature (about20-25° C.) and cationic lipid is added to the final desiredconcentration. dsRNA molecules are added to OptiMEM to the desiredconcentration and the solution is added to the diluted dsRNA andincubated for 15 minutes at room temperature. In dose responseexperiments, the RNA complex is serially diluted into OptiMEM prior toaddition of the cationic lipid.

Animal Models

The efficacy of anti-α-1 antitrypsin dsRNA agents may be evaluated in ananimal model. Animal models of liver diseases, conditions, or disordersas are known in the art can be used for evaluation of the efficacy,potency, toxicity, etc. of anti-α-1 antitrypsin dsRNAs. Exemplaryanimals model of α-1 antitrypsin-induced liver disease are transgenicmice that express human α-1 antitrypsin mutant Z protein, PiZ, whichrecapitulate the human liver disease and exhibit inflammation, increasedlevels of apoptosis and autophagy, accelerated proliferation andenhanced development of hepatic progenitor cells (the behavior of suchmodels also suggest the employment of antioxidants in combination withanti-α-1 antitrypsin dsRNAs in treatment of liver disease; Marcus et al.Exper Biol Med 237: 1163-1172; Teckman et al. Am J Physiol GastrointestLiver Physiol 286: G851-62; Rudnick et al. Hepatology 39: 1048-55; Bruntet al. J Pediatr Gastroenterol Nutr 51: 626-30). Such mice areavailable, for example, from Saint Louis University. These animal modelsmay be used as a source cells or tissue for assays of the compositionsof the invention. Such models can also be used or adapted for use forpre-clinical evaluation of the efficacy of dsRNA compositions of theinvention in modulating α-1 antitrypsin gene expression towardtherapeutic use.

Such models and/or wild-type mice can be used in evaluating the efficacyof dsRNA molecules of the invention to inhibit α-1 antitrypsin levels,expression, development of α-1 antitrypsin-associated phenotypes,diseases or disorders, etc. These models, wild-type mice and/or othermodels can similarly be used to evaluate the safety/toxicity andefficacy of dsRNA molecules of the invention in a pre-clinical setting.

Specific examples of animal model systems useful for evaluation of theα-1 antitrypsin-targeting dsRNAs of the invention include wild-type miceand transgenic PiZ mutant model mice. In an exemplary in vivoexperiment, dsRNAs of the invention are tail vein injected into suchmouse models at doses ranging from 1 to 10 mg/kg or, alternatively,repeated doses are administered at single-dose IC₅₀ levels, and organsamples (e.g., liver, but may also include prostate, kidney, lung,pancreas, colon, skin, spleen, bone marrow, lymph nodes, mammary fatpad, etc.) are harvested 24 hours after administration of the finaldose. Such organs are then evaluated for mouse and/or human α-1antitrypsin levels, depending upon the model used. Duration of actioncan also be examined at, e.g., 1, 4, 7, 14, 21 or more days after finaldsRNA administration.

α-1 Antitrypsin-Targeting dsRNAs

In certain embodiments, an anti-α-1 antitrypsin DsiRNA of the instantinvention possesses strand lengths of at least 25 nucleotides.Accordingly, in certain embodiments, an anti-α-1 antitrypsin DsiRNAcontains one oligonucleotide sequence, a first sequence, that is atleast 25 nucleotides in length and no longer than 35 or up to 50 or morenucleotides. This sequence of RNA can be between 26 and 35, 26 and 34,26 and 33, 26 and 32, 26 and 31, 26 and 30, and 26 and 29 nucleotides inlength. This sequence can be 27 or 28 nucleotides in length or 27nucleotides in length. The second sequence of the DsiRNA agent can be asequence that anneals to the first sequence under biological conditions,such as within the cytoplasm of a eukaryotic cell. Generally, the secondoligonucleotide sequence will have at least 19 complementary base pairswith the first oligonucleotide sequence, more typically the secondoligonucleotide sequence will have 21 or more complementary base pairs,or 25 or more complementary base pairs with the first oligonucleotidesequence. In one embodiment, the second sequence is the same length asthe first sequence, and the DsiRNA agent is blunt ended. In anotherembodiment, the ends of the DsiRNA agent have one or more overhangs.

In certain embodiments, the first and second oligonucleotide sequencesof the DsiRNA agent exist on separate oligonucleotide strands that canbe and typically are chemically synthesized. In some embodiments, bothstrands are between 26 and 35 nucleotides in length. In otherembodiments, both strands are between 25 and 30 or 26 and 30 nucleotidesin length. In one embodiment, both strands are 27 nucleotides in length,are completely complementary and have blunt ends. In certain embodimentsof the instant invention, the first and second sequences of an anti-α-1antitrypsin DsiRNA exist on separate RNA oligonucleotides (strands). Inone embodiment, one or both oligonucleotide strands are capable ofserving as a substrate for Dicer. In other embodiments, at least onemodification is present that promotes Dicer to bind to thedouble-stranded RNA structure in an orientation that maximizes thedouble-stranded RNA structure's effectiveness in inhibiting geneexpression. In certain embodiments of the instant invention, theanti-α-1 antitrypsin DsiRNA agent is comprised of two oligonucleotidestrands of differing lengths, with the anti-α-1 antitrypsin DsiRNApossessing a blunt end at the 3′ terminus of a first strand (sensestrand) and a 3′ overhang at the 3′ terminus of a second strand(antisense strand). The DsiRNA can also contain one or moredeoxyribonucleic acid (DNA) base substitutions.

Suitable DsiRNA compositions that contain two separate oligonucleotidescan be chemically linked outside their annealing region by chemicallinking groups. Many suitable chemical linking groups are known in theart and can be used. Suitable groups will not block Dicer activity onthe DsiRNA and will not interfere with the directed destruction of theRNA transcribed from the target gene. Alternatively, the two separateoligonucleotides can be linked by a third oligonucleotide such that ahairpin structure is produced upon annealing of the two oligonucleotidesmaking up the DsiRNA composition. The hairpin structure will not blockDicer activity on the DsiRNA and will not interfere with the directeddestruction of the target RNA.

The dsRNA molecule can be designed such that every residue of theantisense strand is complementary to a residue in the target molecule.Alternatively, substitutions can be made within the molecule to increasestability and/or enhance processing activity of said molecule.Substitutions can be made within the strand or can be made to residuesat the ends of the strand. In certain embodiments, substitutions and/ormodifications are made at specific residues within a DsiRNA agent. Suchsubstitutions and/or modifications can include, e.g.,deoxy-modifications at one or more residues of positions 1, 2 and 3 whennumbering from the 3′ terminal position of the sense strand of a DsiRNAagent; and introduction of 2′-O-alkyl (e.g., 2′-O-methyl) modificationsat the 3′ terminal residue of the antisense strand of DsiRNA agents,with such modifications also being performed at overhang positions ofthe 3′ portion of the antisense strand and at alternating residues ofthe antisense strand of the DsiRNA that are included within the regionof a DsiRNA agent that is processed to form an active siRNA agent. Thepreceding modifications are offered as exemplary, and are not intendedto be limiting in any manner. Further consideration of the structure ofpreferred DsiRNA agents, including further description of themodifications and substitutions that can be performed upon the anti-α-1antitrypsin DsiRNA agents of the instant invention, can be found below.

A dsRNA of the invention comprises two RNA strands that are sufficientlycomplementary to hybridize to form a duplex structure. One strand of thedsRNA (the antisense strand) comprises a region of complementarity thatis substantially complementary, and generally fully complementary, to atarget sequence, derived from the sequence of an mRNA formed during theexpression of the α-1 antitrypsin target gene, the other strand (thesense strand) comprises a region which is complementary to the antisensestrand, such that the two strands hybridize and form a duplex structurewhen combined under suitable conditions. Generally, the duplex structureis between 15 and 35, optionally between 25 and 30, between 26 and 30,between 18 and 25, between 19 and 24, or between 19 and 21 base pairs inlength. Similarly, the region of complementarity to the target sequenceis between 15 and 35, optionally between 18 and 30, between 25 and 30,between 19 and 24, or between 19 and 21 nucleotides in length. The dsRNAof the invention may further comprise one or more single-strandednucleotide overhang(s). It has been identified that dsRNAs comprisingduplex structures of between 15 and 35 base pairs in length can beeffective in inducing RNA interference, including DsiRNAs (generally ofat least 25 base pairs in length) and siRNAs (in certain embodiments,duplex structures of siRNAs are between 20 and 23, and optionally,specifically 21 base pairs (Elbashir et al., EMBO 20: 6877-6888)). Ithas also been identified that dsRNAs possessing duplexes shorter than 20base pairs can be effective as well (e.g., 15, 16, 17, 18 or 19 basepair duplexes). In certain embodiments, the dsRNAs of the invention cancomprise at least one strand of a length of 19 nucleotides or more. Incertain embodiments, it can be reasonably expected that shorter dsRNAscomprising a sequence complementary to one of the sequences of Tables 5,10, 15 or 20, minus only a few nucleotides on one or both ends may besimilarly effective as compared to the dsRNAs described above and inTables 2-3, 7-8, 12-13 and 17-18. Hence, dsRNAs comprising a partialsequence of at least 15, 16, 17, 18, 19, 20, or more contiguousnucleotides sufficiently complementary to one of the sequences of Tables5, 10, 15 or 20, and differing in their ability to inhibit theexpression of the α-1 antitrypsin target gene in an assay as describedherein by not more than 5, 10, 15, 20, 25, or 30% inhibition from adsRNA comprising the full sequence, are contemplated by the invention.In one embodiment, at least one end of the dsRNA has a single-strandednucleotide overhang of 1 to 5, optionally 1 to 4, in certainembodiments, 1 or 2 nucleotides. Certain dsRNA structures having atleast one nucleotide overhang possess superior inhibitory properties ascompared to counterparts possessing base-paired blunt ends at both endsof the dsRNA molecule.

In one embodiment, dsRNA molecules of the invention that down regulateor reduce α-1 antitrypsin gene expression are used for treating,preventing or reducing α-1 antitrypsin-related diseases or disorders(e.g., liver disease) in a subject or organism.

In one embodiment of the present invention, each sequence of a DsiRNAmolecule of the invention is independently 25 to 35 nucleotides inlength, in specific embodiments 25, 26, 27, 28, 29, 30, 31, 32, 33, 34or 35 nucleotides in length. In another embodiment, the DsiRNA duplexesof the invention independently comprise 25 to 30 base pairs (e.g., 25,26, 27, 28, 29, or 30). In another embodiment, one or more strands ofthe DsiRNA molecule of the invention independently comprises 19 to 35nucleotides (e.g., 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31,32, 33, 34 or 35) that are complementary to a target (α-1 antitrypsin)nucleic acid molecule. In certain embodiments, a DsiRNA molecule of theinvention possesses a length of duplexed nucleotides between 25 and 34nucleotides in length (e.g., 25, 26, 27, 28, 29, 30, 31, 32, 33 or 34nucleotides in length; optionally, all such nucleotides base pair withcognate nucleotides of the opposite strand). (Exemplary DsiRNA moleculesof the invention are shown in FIG. 1 , and below).

In certain additional embodiments of the present invention, eacholigonucleotide of a DsiRNA molecule of the invention is independently25 to 53 nucleotides in length, in specific embodiments 25, 26, 27, 28,29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46,47, 48, 49, 50, 51, 52 or 53 nucleotides in length. For DsiRNAspossessing a strand that exceeds 30 nucleotides in length, availablestructures include those where only one strand exceeds 30 nucleotides inlength (see, e.g., U.S. Pat. No. 8,349,809), or those where both strandsexceed 30 nucleotides in length (see, e.g., WO 2010/080129). Stabilizingmodifications (e.g., 2′-O-Methyl, phosphorothioate,deoxyribonucleotides, including dNTP base pairs, etc.) can beincorporated within any double stranded nucleic acid of the invention,and can be used in particular within DsiRNAs possessing one or bothstrands exceeding 30 nucleotides in length. While the guide strand of adouble stranded nucleic acid of the invention must possess a sequenceof, e.g., 15, 16, 17, 18 or 19 nucleotides that are complementary to atarget RNA (e.g., mRNA), additional sequence(s) of the guide strand neednot be complementary to the target RNA. The end structures of doublestranded nucleic acids possessing at least one strand length in excessof 30 nucleotides can also be varied while continuing to yieldfunctional dsNAs—e.g. the 5′ end of the guide strand and the 3′ end ofthe passenger strand may form a 5′-overhang, a blunt end or a 3′overhang (for certain dsNAs, e.g., “single strand extended” dsNAs, thelength of such a 5′ or 3′ overhang can be 1-4, 1-5, 1-6, 1-10, 1-15,1-20 or even 1-25 or more); similarly, the 3′ end of the guide strandand the 5′ end of the passenger strand may form a 5′-overhang, a bluntend or a 3′ overhang (for certain dsNAs, e.g., “single strand extended”dsNAs, the length of such a 5′ or 3′ overhang can be 1-4, 1-5, 1-6,1-10, 1-15, 1-20 or even 1-25 or more). In certain embodiments, thelength of the passenger strand is 31-49 nucleotides while the length ofthe guide strand is 31-53 nucleotides, optionally while the 5′ end ofthe guide strand forms a blunt end (optionally, a base-paired blunt end)with the 3′ end of the passenger strand, optionally, with the 3′ end ofthe guide strand and the 5′ end of the passenger strand forming a 3′overhang of 1-4 nucleotides in length. Exemplary “extended” Dicersubstrate structures are set forth, e.g., in US 2010/0173974 and U.S.Pat. No. 8,349,809, both of which are incorporated herein by reference.In certain embodiments, one or more strands of the dsNA molecule of theinvention independently comprises 19 to 35 nucleotides (e.g., 19, 20,21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34 or 35) that arecomplementary to a target (α-1 antitrypsin) nucleic acid molecule. Incertain embodiments, a DsiRNA molecule of the invention possesses alength of duplexed nucleotides between 25 and 49 nucleotides in length(e.g., 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40,41, 42, 43, 44, 45, 46, 47, 48 or 49 nucleotides in length; optionally,all such nucleotides base pair with cognate nucleotides of the oppositestrand).

In certain embodiments, a DsiRNA (in a state as initially formed, priorto dicer cleavage) is more potent at reducing α-1 antitrypsin targetgene expression in a mammalian cell than a 19, 20, 21, 22 or 23 basepair sequence that is contained within it. In certain such embodiments,a DsiRNA prior to dicer cleavage is more potent than a 19-21mercontained within it. Optionally, a DsiRNA prior to dicer cleavage ismore potent than a 19 base pair duplex contained within it that issynthesized with symmetric dTdT overhangs (thereby forming a siRNApossessing 21 nucleotide strand lengths having dTdT overhangs). Incertain embodiments, the DsiRNA is more potent than a 19-23mer siRNA(e.g., a 19 base pair duplex with dTdT overhangs) that targets at least19 nucleotides of the 21 nucleotide target sequence that is recited fora DsiRNA of the invention (without wishing to be bound by theory, theidentity of a such a target site for a DsiRNA is identified viaidentification of the Ago2 cleavage site for the DsiRNA; once the Ago2cleavage site of a DsiRNA is determined for a DsiRNA, identification ofthe Ago2 cleavage site for any other inhibitory dsRNA can be performedand these Ago2 cleavage sites can be aligned, thereby determining thealignment of projected target nucleotide sequences for multiple dsRNAs).In certain related embodiments, the DsiRNA is more potent than a19-23mer siRNA that targets at least 20 nucleotides of the 21 nucleotidetarget sequence that is recited for a DsiRNA of the invention.Optionally, the DsiRNA is more potent than a 19-23mer siRNA that targetsthe same 21 nucleotide target sequence that is recited for a DsiRNA ofthe invention. In certain embodiments, the DsiRNA is more potent thanany 21mer siRNA that targets the same 21 nucleotide target sequence thatis recited for a DsiRNA of the invention. Optionally, the DsiRNA is morepotent than any 21 or 22mer siRNA that targets the same 21 nucleotidetarget sequence that is recited for a DsiRNA of the invention. Incertain embodiments, the DsiRNA is more potent than any 21, 22 or 23mersiRNA that targets the same 21 nucleotide target sequence that isrecited for a DsiRNA of the invention. As noted above, such potencyassessments are most effectively performed upon dsRNAs that are suitablyformulated (e.g., formulated with an appropriate transfection reagent)at a concentration of 1 nM or less. Optionally, an IC₅₀ assessment isperformed to evaluate activity across a range of effective inhibitoryconcentrations, thereby allowing for robust comparison of the relativepotencies of dsRNAs so assayed.

The dsRNA molecules of the invention are added directly, or can becomplexed with lipids (e.g., cationic lipids), packaged withinliposomes, or otherwise delivered to target cells or tissues. Thenucleic acid or nucleic acid complexes can be locally administered torelevant tissues ex vivo, or in vivo through direct dermal application,transdermal application, or injection, with or without theirincorporation in biopolymers. In particular embodiments, the nucleicacid molecules of the invention comprise sequences shown in FIG. 1 , andthe below exemplary structures. Examples of such nucleic acid moleculesconsist essentially of sequences defined in these figures and exemplarystructures. Furthermore, where such agents are modified in accordancewith the below description of modification patterning of DsiRNA agents,chemically modified forms of constructs described in FIG. 1 , and thebelow exemplary structures can be used in all uses described for theDsiRNA agents of FIG. 1 , and the below exemplary structures.

In another aspect, the invention provides mammalian cells containing oneor more dsRNA molecules of this invention. The one or more dsRNAmolecules can independently be targeted to the same or different sites.

Modified Structures of Anti-α-1 Antitrypsin DsiRNA Agents

In certain embodiments, the anti-α-1 antitrypsin DsiRNA agents of theinvention can have the following structures:

In one such embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “Y” is an overhang domain comprised of 1-4 RNAmonomers that are optionally 2′-O-methyl RNA monomers. In a relatedembodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “Y” is an overhang domain comprised of 1-4 RNA monomersthat are optionally 2′-O-methyl RNA monomers, and “D”=DNA. In oneembodiment, the top strand is the sense strand, and the bottom strand isthe antisense strand. Alternatively, the bottom strand is the sensestrand and the top strand is the antisense strand.

DsiRNAs of the invention can carry a broad range of modificationpatterns (e.g., 2′-O-methyl RNA patterns, e.g., within extended DsiRNAagents). Certain modification patterns of the second strand of DsiRNAsof the invention are presented below.

In one embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. In arelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′

wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers, and“D”=DNA. The top strand is the sense strand, and the bottom strand isthe antisense strand.

In another such embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. In arelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand.

In another such embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. In arelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. In arelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. In a further relatedembodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M7” or “M7”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. In arelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. The top strand is the sense strand, and the bottomstrand is the antisense strand.

In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M6” or “M6”modification pattern.

In other embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In a related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In anotherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M5” or “M5”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In a related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In one related embodiment, the DsiRNA comprises:

  5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

  5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M4” or “M4”modification pattern.

In additional embodiments, the DsiRNA comprises:

  5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In a related embodiment, the DsiRNA comprises:

  5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

  5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

  5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M8” or “M8”modification pattern.

In other embodiments, the DsiRNA comprises:

  5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

  5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

  5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

  5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M3” or “M3”modification pattern.

In additional embodiments, the DsiRNA comprises:

  5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In a related embodiment, the DsiRNA comprises:

  5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

  5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

  5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M2” or “M2”modification pattern.

In further embodiments, the DsiRNA comprises:

  5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In a related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M1” or “M1”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M9” or “M9”modification pattern.

In other embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In a related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M10” or “M10”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M11” or “M11”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M12” or “M12”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M13” or “M13”modification pattern.

In other embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M21” or “M21”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M14” or “M14”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M15” or “M15”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In a related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M16” or “M16”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M17” or “M17”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M18” or “M18”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M19” or “M19”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5 ′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5 ′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M20” or “M20”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M22” or “M22”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M24” or “M24”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M25” or “M25”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5 ′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5 ′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M26” or “M26”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M27” or “M27”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M28” or “M28”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M29” or “M29”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M30” or “M30”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M31” or “M31”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M32” or “M32”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M34” or “M34”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′ -YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M35” or “M35”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M37” or “M37”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M38” or “M38”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M40” or “M40”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M41” or “M41”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M36” or “M36”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M42” or “M42”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M43” or “M43”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M44” or “M44”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M45” or “M45”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M46” or “M46”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M47” or “M47”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M48” or “M48”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M52” or “M52”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M54” or “M54”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M55” or “M55”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M56” or “M56”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M57” or “M57”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M58” or “M58”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M59” or “M59”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M60” or “M60”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M61” or “M61”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M62” or “M62”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M63” or “M63”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M64” or “M64”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M65” or “M65”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M66” or “M66”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M67” or “M67”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M68” or “M68”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5 ′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M69” or “M69”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M70” or “M70”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M71” or “M71”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M72” or “M72”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M73” or “M73”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. In a further relatedembodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M7*” or “M7*”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M6*” or “M6*”modification pattern.

In other embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In anotherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M5*” or “M5*”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M4*” or “M4*”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M8*” or “M8*”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M2*” or “M2*”modification pattern.

In other embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M10*” or“M10*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M11*” or“M11*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M13*” or“M13*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M14*” or“M14*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M15*” or“M15*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M16*” or“M16*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M17*” or“M17*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M18*” or“M18*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M19*” or“M19*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5 ′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3 -XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M20*” or“M20*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M22*” or“M22*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M24*” or“M24*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M25*” or“M25*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M26*” or“M26*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M27*” or“M27*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M28*” or“M28*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M29*” or“M29*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M34*” or“M34*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M35*” or“M35*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M37*” or“M37*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M38*” or“M38*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M40*” or“M40*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M41*” or“M41*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M36*” or“M36*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M42*” or“M42*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M43*” or“M43*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M44*” or“M44*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M46*” or“M46*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M47*” or“M47*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M48*” or“M48*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M52*” or“M52*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M54*” or“M54*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M55*” or“M55*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M56*” or“M56*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M57*” or“M57*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M58*” or“M58*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M59*” or“M59*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M60*” or“M60*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M61*” or“M61*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M62*” or“M62*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M63*” or“M63*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M64*” or“M64*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M65*” or“M65*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M66*” or“M66*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M67*” or“M67*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M68*” or“M68*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M69*” or“M69*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M70*” or“M70*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M71*” or“M71*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M72*” or“M72*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M73*” or“M73*” modification pattern.

Additional exemplary antisense strand modifications include thefollowing:

3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M74”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M75”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M76”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M77”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M78”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M79”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M80”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M81”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M82”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M83”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M84”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M85”3′-FFFXXXXXXXXXXXXXXXXXXXXFFFF-5′ “AS-M88”3′-XXXXFXXXFXFXXXXXXXXXXXXXXXX-5′ “AS-M89”3′-FFFXFXFXFXFXFXFXFXXXXXXFFFF-5′ “AS-M90”3′-FFFXXXXXXXXXXXXXXXXXXXXXXFF-5′ “AS-M91”3′-XXXXXXFXXXXXFXFXXXXXXXXXXXX-5′ “AS-M92”3′-FFFXFXXXXXXXXXXXXXFXXXXXXXX-5′ “AS-M93”3′-FFFXFXFXXXXXFXFXFXFXXXXFFFF-5′ “AS-M94”3′-FFFXFXFXFXFXFXFXFXXXXXXFFFF-5′ “AS-M95”3′-FFFXFXFXFXFXFXFXFXXXXXXFFFpF-5′ “AS-M96”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M210”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M74*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M75*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M76*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M77*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M78*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M79*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M80*”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M82*”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M83*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M84*”3′-XFFXXXXXXXXXXXXXXXXXXXXFFFF-5′ “AS-M88*”3′-XXXXFXXXFXFXXXXXXXXXXXXXXXX-5* “AS-M89*”3′-XFFXFXFXFXFXFXFXFXXXXXXFFFF-5′ “AS-M90*”3′-XFFXXXXXXXXXXXXXXXXXXXXXXFF-5′ “AS-M91*”3′-XXXXXXFXXXXXFXFXXXXXXXXXXXX-5* “AS-M92*”3′-XFFXFXXXXXXXXXXXXXFXXXXXXXX-5* “AS-M93*”3′-XFFXFXFXXXXXFXFXFXFXXXXFFFF-5′ “AS-M94*”3′-XFFXFXFXFXFXFXFXFXXXXXXFFFF-5′ “AS-M95*”3′-XFFXFXFXFXFXFXFXFXXXXXXFFFpF-5′ “AS-M96*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M210*”where “X”=RNA, “X”=2′-O-methyl RNA, “D”=DNA, “F”=2′-Fluoro NA and“p”=Phosphorothioate linkage.

In certain additional embodiments, the antisense strand of selecteddsRNAs of the invention are extended, optionally at the 5′ end, with anexemplary 5′ extension of base “AS-M8”, “AS-M17” and “AS-M48”modification patterns respectively represented as follows:

(SEQ ID NO: 3493) 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXXU

GCU

UCGT-5′ “AS-M8, extended” (SEQ ID NO: 3493)3′-XXXXXXXXXXXXXXXXXXXXXXXXXXXU

GCU

UCGT-5′ “AS-M17, extended” (SEQ ID NO: 3493)3′-XXXXXXXXXXXXXXXXXXXXXXXXXXXU

GCU

UCGT-5′ “AS-M48, extended”where “X”=RNA; “X”=2′-O-methyl RNA; “F”=2′-Fluoro NA and “A” in bold,italics indicates a 2′-Fluoro-adenine residue.

In certain embodiments, the sense strand of a DsiRNA of the invention ismodified-specific exemplary forms of sense strand modifications areshown below, and it is contemplated that such modified sense strands canbe substituted for the sense strand of any of the DsiRNAs shown above togenerate a DsiRNA comprising a below-depicted sense strand that annealswith an above-depicted antisense strand. Exemplary sense strandmodification patterns include:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM1”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM2”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM3”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM4”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM5”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM6”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM7”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM8”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM9”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM10”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM11”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM12”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM13”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM14”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM15”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM16”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM17”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM18”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM19”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM20”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM21”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM23”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM24”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM25”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM30”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM31”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM32”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM33”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM34”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM35”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM36”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM37”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM38”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM39”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM40”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM41”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM42”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM43”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM44”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM45”, “SM47”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM46”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM48”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM49”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM50”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM51”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM52”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM53”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM54”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM55”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM56”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM57”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM58”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM59”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM60”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM61”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM62”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM63”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM64”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM65”5′-XXXXXXXXXXXXXXXXXXXXXXXpDpD-3′ “SM66”5′-XpXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM67”5′-XpXXXXXXXXXXXXXXXXXXXXXXpDpD-3′ “SM68”5′-DXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM69”5′-DpXXXXXXXXXXXXXXXXXXXXXXpDpD-3′ “SM70”5′-DXDXXXXXXXXXXXXXXXXXXXXDD-3′ “SM71”5′-DpXDXXXXXXXXXXXXXXXXXXXXDD-3′ “SM72”5′-XXDXXXXXXXXXDXXXXXXXXXXDD-3′ “SM73”5′-XpXDXXXXXXXXXDXXXXXXXXXXDD-3′ “SM74”5′-DXDXXXXXXXXXDXXXXXDXXXXDD-3′ “SM75”5′-DpXDXXXXXXXXXDXXXXXDXXXXDD-3′ “SM76”5′-XpXpXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM77”5′-XpXpXXXXXXXXXXXXXXXXXXXXXpDpD-3′ “SM78”5′-DpXpDXXXXXXXXXXXXXXXXXXXXDD-3′ “SM79”5′-XpXpDXXXXXXXXXDXXXXXXXXXXDD-3′ “SM80”5′-DXDXXXDXXXXXDXXXXXDXXXXDD-3′ “SM81”5′-DpXDXXXDXXXXXDXXXXXDXXXXpDpD-3′ “SM82”5′ C3 spacer-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM83”5′ C3 spacer-XXDXXXXXXXXXDXXXXXXXXXXDD-3′ “SM84”5′ C3 spacer-XXXXXXXXXXXXXXXXXXXXXXXpDpD-3′ “SM85”5′-XXXXXXXXXXXXXXXXXXXXXXXpDpD-3′ “SM86”5′-XpXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM87”5′-XpXXXXXXXXXXXXXXXXXXXXXXpDpD-3′ “SM88”5′-DXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM89”5′-DpXXXXXXXXXXXXXXXXXXXXXXpDpD-3′ “SM90”5′-DXDXXXXXXXXXXXXXXXXXXXXDD-3′ “SM91”5′-DpXDXXXXXXXXXXXXXXXXXXXXDD-3′ “SM92”5′-XXDXXXXXXXXXDXXXXXXXXXXDD-3′ “SM93”5′-XpXDXXXXXXXXXDXXXXXXXXXXDD-3′ “SM94”5′-DXDXXXXXXXXXDXXXXXDXXXXDD-3′ “SM95”5′-DpXDXXXXXXXXXDXXXXXDXXXXDD-3′ “SM96”5′-XpXpXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM97”5′-XpXpXXXXXXXXXXXXXXXXXXXXXpDpD-3′ “SM98”5′-DpXpDXXXXXXXXXXXXXXXXXXXXDD-3′ “SM99”5′-XpXpDXXXXXXXXXDXXXXXXXXXXDD-3′ “SM100”5′-DXDXXXXXXXXXDXDXXXDDXXDDD-3′ “SM101”5′-DpXDXXXDXXXXXDXXXXXDXXXXpDpD-3′ “SM102”5′ C3 spacer-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM103”5′ C3 spacer-XXDXXXXXXXXXDXXXXXXXXXXDD-3′ “SM104”5′ C3 spacer-XXXXXXXXXXXXXXXXXXXXXXXpDpD-3′ “SM105”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM106”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM107”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM108”5′-XFXXXXXXXXXXXXXXXFXXXXXDD-3′ “SM110”5′-XXXFXFXXXXXXXFXXXXXXXXXDD-3′ “SM111”5′-XFXFXFXFXXXFXFXFXFXXXXXDD-3′ “SM112”5′-XpFXFXFXFXXXFXFXFXFXXXXXpDpD-3′ “SM113”5′-XFXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM114”5′-XXXXFFXFXXXFXFXXXXXXXXXDD-3′ “SM115”5′-XFXFXXXXXXXXXXXXFXXXXXXDD-3′ “SM116”5′-XFXFFFXFXXXFXFXFFFXXXXXDD-3′ “SM117”5′-XFXFXFXFXXXFXFXFXFXXXXXDD-3′ “SM118”5′-XpFXFXFXFXXXFXFXFXFXXXXXpDpD-3′ “SM119”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM250”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM251”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM252” 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ “SM22”5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′where “X”=RNA, “X”=2′-O-methyl RNA, “D”=DNA, “F”=2′-Fluoro NA and“p”=Phosphorothioate linkage.

The above modification patterns can also be incorporated into, e.g., theextended DsiRNA structures and mismatch and/or frayed DsiRNA structuresdescribed below.

In another embodiment, the DsiRNA comprises strands having equal lengthspossessing 1-3 mismatched residues that serve to orient Dicer cleavage(specifically, one or more of positions 1, 2 or 3 on the first strand ofthe DsiRNA, when numbering from the 3′-terminal residue, are mismatchedwith corresponding residues of the 5′-terminal region on the secondstrand when first and second strands are annealed to one another). Anexemplary 27mer DsiRNA agent with two terminal mismatched residues isshown:

wherein “X”=RNA, “M”=Nucleic acid residues (RNA, DNA or non-natural ormodified nucleic acids) that do not base pair (hydrogen bond) withcorresponding “M” residues of otherwise complementary strand whenstrands are annealed. Any of the residues of such agents can optionallybe 2′-O-methyl RNA monomers—alternating positioning of 2′-O-methyl RNAmonomers that commences from the 3′-terminal residue of the bottom(second) strand, as shown for above asymmetric agents, can also be usedin the above “blunt/fray” DsiRNA agent. In one embodiment, the topstrand is the sense strand, and the bottom strand is the antisensestrand. Alternatively, the bottom strand is the sense strand and the topstrand is the antisense strand.

In certain additional embodiments, the present invention providescompositions for RNA interference (RNAi) that possess one or more basepaired deoxyribonucleotides within a region of a double strandedribonucleic acid (dsRNA) that is positioned 3′ of a projected sensestrand Dicer cleavage site and correspondingly 5′ of a projectedantisense strand Dicer cleavage site. The compositions of the inventioncomprise a dsRNA which is a precursor molecule, i.e., the dsRNA of thepresent invention is processed in vivo to produce an active smallinterfering nucleic acid (siRNA). The dsRNA is processed by Dicer to anactive siRNA which is incorporated into RISC.

In certain embodiments, the DsiRNA agents of the invention can have thefollowing exemplary structures (noting that any of the followingexemplary structures can be combined, e.g., with the bottom strandmodification patterns of the above-described structures—in one specificexample, the bottom strand modification pattern shown in any of theabove structures is applied to the 27 most 3′ residues of the bottomstrand of any of the following structures; in another specific example,the bottom strand modification pattern shown in any of the abovestructures upon the 23 most 3′ residues of the bottom strand is appliedto the 23 most 3′ residues of the bottom strand of any of the followingstructures):

In one such embodiment, the DsiRNA comprises the following (an exemplary“right-extended”, “DNA extended” DsiRNA):

5′-XXXXXXXXXXXXXXXXXXXXXXXX_(N)*D_(N)DD-3′3′-YXXXXXXXXXXXXXXXXXXXXXXXX_(N)*D_(N)XX-5′wherein “X”=RNA, “Y” is an optional overhang domain comprised of 0-10RNA monomers that are optionally 2′-O-methyl RNA monomers—in certainembodiments, “Y” is an overhang domain comprised of 1-4 RNA monomersthat are optionally 2′-O-methyl RNA monomers, “D”=DNA, and “N”=1 to 50or more, but is optionally 1-8 or 1-10. “N*”=0 to 15 or more, but isoptionally 0, 1, 2, 3, 4, 5 or 6. In one embodiment, the top strand isthe sense strand, and the bottom strand is the antisense strand.Alternatively, the bottom strand is the sense strand and the top strandis the antisense strand.

In a related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXX_(N)*D_(N)DD-3′3′-YXXXXXXXXXXXXXXXXXXXXXXXX_(N)*D_(N)DD-5′wherein “X”=RNA, “Y” is an optional overhang domain comprised of 0-10RNA monomers that are optionally 2′-O-methyl RNA monomers—in certainembodiments, “Y” is an overhang domain comprised of 1-4 RNA monomersthat are optionally 2′-O-methyl RNA monomers, “D”=DNA, and “N”=1 to 50or more, but is optionally 1-8 or 1-10. “N*”=0 to 15 or more, but isoptionally 0, 1, 2, 3, 4, 5 or 6. In one embodiment, the top strand isthe sense strand, and the bottom strand is the antisense strand.Alternatively, the bottom strand is the sense strand and the top strandis the antisense strand.

In an additional embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXX_(N)*D_(N)DD-3′3′-YXXXXXXXXXXXXXXXXXXXXXXXX_(N)*D_(N)ZZ-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an optional overhang domaincomprised of 0-10 RNA monomers that are optionally 2′-O-methyl RNAmonomers—in certain embodiments, “Y” is an overhang domain comprised of1-4 RNA monomers that are optionally 2′-O-methyl RNA monomers, “D”=DNA,“Z”=DNA or RNA, and “N”=1 to 50 or more, but is optionally 1-8 or 1-10.“N*”=0 to 15 or more, but is optionally 0, 1, 2, 3, 4, 5 or 6. In oneembodiment, the top strand is the sense strand, and the bottom strand isthe antisense strand. Alternatively, the bottom strand is the sensestrand and the top strand is the antisense strand, with 2′-O-methyl RNAmonomers located at alternating residues along the top strand, ratherthan the bottom strand presently depicted in the above schematic.

In another such embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXX_(N*)D_(N)DD-3′3′-YXXXXXXXXXXXXXXXXXXXXXXXX_(N*)D_(N)ZZ-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an optional overhang domaincomprised of 0-10 RNA monomers that are optionally 2′-O-methyl RNAmonomers—in certain embodiments, “Y” is an overhang domain comprised of1-4 RNA monomers that are optionally 2′-O-methyl RNA monomers, “D”=DNA,“Z”=DNA or RNA, and “N”=1 to 50 or more, but is optionally 1-8 or 1-10.“N*”=0 to 15 or more, but is optionally 0, 1, 2, 3, 4, 5 or 6. In oneembodiment, the top strand is the sense strand, and the bottom strand isthe antisense strand. Alternatively, the bottom strand is the sensestrand and the top strand is the antisense strand, with 2′-O-methyl RNAmonomers located at alternating residues along the top strand, ratherthan the bottom strand presently depicted in the above schematic.

In another such embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXX_(N*)D_(N)DD-3′3′-YXXXXXXXXXXXXXXXXXXXXXXXX_(N*)D_(N)ZZ-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an optional overhang domaincomprised of 0-10 RNA monomers that are optionally 2′-O-methyl RNAmonomers—in certain embodiments, “Y” is an overhang domain comprised of1-4 RNA monomers that are optionally 2′-O-methyl RNA monomers, “D”=DNA,“Z”=DNA or RNA, and “N”=1 to 50 or more, but is optionally 1-8 or 1-10.“N*”=0 to 15 or more, but is optionally 0, 1, 2, 3, 4, 5 or 6. In oneembodiment, the top strand is the sense strand, and the bottom strand isthe antisense strand. Alternatively, the bottom strand is the sensestrand and the top strand is the antisense strand, with 2′-O-methyl RNAmonomers located at alternating residues along the top strand, ratherthan the bottom strand presently depicted in the above schematic.

In another embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXX_(N*)[X1/D1]_(N)DD-3′3′-YXXXXXXXXXXXXXXXXXXXXXXXX_(N*)[X2/D2]_(N)ZZ-5′wherein “X”=RNA, “Y” is an optional overhang domain comprised of 0-10RNA monomers that are optionally 2′-O-methyl RNA monomers—in certainembodiments, “Y” is an overhang domain comprised of 1-4 RNA monomersthat are optionally 2′-O-methyl RNA monomers, “D”=DNA, “Z”=DNA or RNA,and “N”=1 to 50 or more, but is optionally 1-8 or 1-10, where at leastone D1_(N) is present in the top strand and is base paired with acorresponding D2_(N) in the bottom strand. Optionally, D1_(N) andD1_(N+1) are base paired with corresponding D2_(N) and D2_(N+1); D1_(N),D1_(N+1) and D1_(N+2) are base paired with corresponding D2_(N),D1_(N+1) and D1_(N+2), etc. “N*”=0 to 15 or more, but is optionally 0,1, 2, 3, 4, 5 or 6. In one embodiment, the top strand is the sensestrand, and the bottom strand is the antisense strand. Alternatively,the bottom strand is the sense strand and the top strand is theantisense strand, with 2′-O-methyl RNA monomers located at alternatingresidues along the top strand, rather than the bottom strand presentlydepicted in the above schematic.

In the structures depicted herein, the 5′ end of either the sense strandor antisense strand can optionally comprise a phosphate group.

In another embodiment, a DNA:DNA-extended DsiRNA comprises strandshaving equal lengths possessing 1-3 mismatched residues that serve toorient Dicer cleavage (specifically, one or more of positions 1, 2 or 3on the first strand of the DsiRNA, when numbering from the 3′-terminalresidue, are mismatched with corresponding residues of the 5′-terminalregion on the second strand when first and second strands are annealedto one another). An exemplary DNA:DNA-extended DsiRNA agent with twoterminal mismatched residues is shown:

wherein “X”=RNA, “M”=Nucleic acid residues (RNA, DNA or non-natural ormodified nucleic acids) that do not base pair (hydrogen bond) withcorresponding “M” residues of otherwise complementary strand whenstrands are annealed, “D”=DNA and “N”=1 to 50 or more, but is optionally1-15 or, optionally, 1-8. “N*”=0 to 15 or more, but is optionally 0, 1,2, 3, 4, 5 or 6. Any of the residues of such agents can optionally be2′-O-methyl RNA monomers—alternating positioning of 2′-O-methyl RNAmonomers that commences from the 3′-terminal residue of the bottom(second) strand, as shown for above asymmetric agents, can also be usedin the above “blunt/fray” DsiRNA agent. In one embodiment, the topstrand (first strand) is the sense strand, and the bottom strand (secondstrand) is the antisense strand. Alternatively, the bottom strand is thesense strand and the top strand is the antisense strand. Modificationand DNA:DNA extension patterns paralleling those shown above forasymmetric/overhang agents can also be incorporated into such“blunt/frayed” agents.

In one embodiment, a length-extended DsiRNA agent is provided thatcomprises deoxyribonucleotides positioned at sites modeled to functionvia specific direction of Dicer cleavage, yet which does not require thepresence of a base-paired deoxyribonucleotide in the dsRNA structure. Anexemplary structure for such a molecule is shown:

5′-XXXXXXXXXXXXXXXXXXXDDXX-3′ 3′-YXXXXXXXXXXXXXXXXXDDXXXX-5'wherein “X”=RNA, “Y” is an optional overhang domain comprised of 0-10RNA monomers that are optionally 2′-O-methyl RNA monomers—in certainembodiments, “Y” is an overhang domain comprised of 1-4 RNA monomersthat are optionally 2′-O-methyl RNA monomers, and “D”=DNA. In oneembodiment, the top strand is the sense strand, and the bottom strand isthe antisense strand. Alternatively, the bottom strand is the sensestrand and the top strand is the antisense strand. The above structureis modeled to force Dicer to cleave a minimum of a 21mer duplex as itsprimary post-processing form. In embodiments where the bottom strand ofthe above structure is the antisense strand, the positioning of twodeoxyribonucleotide residues at the ultimate and penultimate residues ofthe 5′ end of the antisense strand will help reduce off-target effects(as prior studies have shown a 2′-O-methyl modification of at least thepenultimate position from the 5′ terminus of the antisense strand toreduce off-target effects; see, e.g., US 2007/0223427).

In one embodiment, the DsiRNA comprises the following (an exemplary“left-extended”, “DNA extended” DsiRNA):

5′-D_(N)XXXXXXXXXXXXXXXXXXXXXXXX_(N*)Y-3′3′-D_(N)XXXXXXXXXXXXXXXXXXXXXXXX_(N*)-5′wherein “X”=RNA, “Y” is an optional overhang domain comprised of 0-10RNA monomers that are optionally 2′-O-methyl RNA monomers—in certainembodiments, “Y” is an overhang domain comprised of 1-4 RNA monomersthat are optionally 2′-O-methyl RNA monomers, “D”=DNA, and “N”=1 to 50or more, but is optionally 1-8 or 1-10. “N*”=0 to 15 or more, but isoptionally 0, 1, 2, 3, 4, 5 or 6. In one embodiment, the top strand isthe sense strand, and the bottom strand is the antisense strand.Alternatively, the bottom strand is the sense strand and the top strandis the antisense strand.

In a related embodiment, the DsiRNA comprises:

5′-D_(N)XXXXXXXXXXXXXXXXXXXXXXXX_(N*)DD-3′3′-D_(N)XXXXXXXXXXXXXXXXXXXXXXXX_(N*)XX-5′wherein “X”=RNA, optionally a 2′-O-methyl RNA monomers “D”=DNA, “N”=1 to50 or more, but is optionally 1-8 or 1-10. “N*”=0 to 15 or more, but isoptionally 0, 1, 2, 3, 4, 5 or 6. In one embodiment, the top strand isthe sense strand, and the bottom strand is the antisense strand.Alternatively, the bottom strand is the sense strand and the top strandis the antisense strand.

In an additional embodiment, the DsiRNA comprises:

5′-D_(N)XXXXXXXXXXXXXXXXXXXXXXXX_(N*)DD-3′ 3′-D_(N)XXXXXXXXXXXXXXXXXXXXXXXX_(N*)ZZ-5′wherein “X”=RNA, optionally a 2′-O-methyl RNA monomers “D”=DNA, “N”=1 to50 or more, but is optionally 1-8 or 1-10. “N*”=0 to 15 or more, but isoptionally 0, 1, 2, 3, 4, 5 or 6. “Z”=DNA or RNA. In one embodiment, thetop strand is the sense strand, and the bottom strand is the antisensestrand. Alternatively, the bottom strand is the sense strand and the topstrand is the antisense strand, with 2′-O-methyl RNA monomers located atalternating residues along the top strand, rather than the bottom strandpresently depicted in the above schematic.

In another such embodiment, the DsiRNA comprises:

5′-D_(N)XXXXXXXXXXXXXXXXXXXXXXXX_(N*)DD-3′ 3′-D_(N)XXXXXXXXXXXXXXXXXXXXXXXX_(N*)ZZ-5′wherein “X”=RNA, optionally a 2′-O-methyl RNA monomers “D”=DNA, “N”=1 to50 or more, but is optionally 1-8 or 1-10. “N*”=0 to 15 or more, but isoptionally 0, 1, 2, 3, 4, 5 or 6. “Z”=DNA or RNA. In one embodiment, thetop strand is the sense strand, and the bottom strand is the antisensestrand. Alternatively, the bottom strand is the sense strand and the topstrand is the antisense strand, with 2′-O-methyl RNA monomers located atalternating residues along the top strand, rather than the bottom strandpresently depicted in the above schematic.

In another such embodiment, the DsiRNA comprises:

5′-D_(N)ZZXXXXXXXXXXXXXXXXXXXXXXXX_(N*)DD-3′ 3′-D_(N)XXXXXXXXXXXXXXXXXXXXXXXXXX_(N*)ZZ-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “D”=DNA, “Z”=DNA or RNA, and “N”=1to 50 or more, but is optionally 1-8 or 1-10. “N*”=0 to 15 or more, butis optionally 0, 1, 2, 3, 4, 5 or 6. In one embodiment, the top strandis the sense strand, and the bottom strand is the antisense strand.Alternatively, the bottom strand is the sense strand and the top strandis the antisense strand, with 2′-O-methyl RNA monomers located atalternating residues along the top strand, rather than the bottom strandpresently depicted in the above schematic.

In another such embodiment, the DsiRNA comprises:

5′-D_(N)ZZXXXXXXXXXXXXXXXXXXXXXXXX_(N*)Y-3′ 3′-D_(N)XXXXXXXXXXXXXXXXXXXXXXXXXX_(N*)-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “D”=DNA, “Z”=DNA or RNA, and “N”=1to 50 or more, but is optionally 1-8 or 1-10. “N*”=0 to 15 or more, butis optionally 0, 1, 2, 3, 4, 5 or 6. “Y” is an optional overhang domaincomprised of 0-10 RNA monomers that are optionally 2′-O-methyl RNAmonomers—in certain embodiments, “Y” is an overhang domain comprised of1-4 RNA monomers that are optionally 2′-O-methyl RNA monomers. In oneembodiment, the top strand is the sense strand, and the bottom strand isthe antisense strand. Alternatively, the bottom strand is the sensestrand and the top strand is the antisense strand, with 2′-O-methyl RNAmonomers located at alternating residues along the top strand, ratherthan the bottom strand presently depicted in the above schematic.

In another embodiment, the DsiRNA comprises:

5′-[X1/D1]_(N)XXXXXXXXXXXXXXXXXXXXXXXX_(N*)DD-3′3′-[X2/D2]_(N)XXXXXXXXXXXXXXXXXXXXXXXX_(N*)ZZ-5′wherein “X”=RNA, “D”=DNA, “Z”=DNA or RNA, and “N”=1 to 50 or more, butis optionally 1-8 or 1-10, where at least one D1_(N) is present in thetop strand and is base paired with a corresponding D2_(N) in the bottomstrand. Optionally, D1_(N) and D1_(N+1) are base paired withcorresponding D2_(N) and D2_(N+1); D1_(N), D1_(N+1) and D1_(N+2) arebase paired with corresponding D2_(N), D1_(N+1) and D1_(N+2), etc.“N*”=0 to 15 or more, but is optionally 0, 1, 2, 3, 4, 5 or 6. In oneembodiment, the top strand is the sense strand, and the bottom strand isthe antisense strand. Alternatively, the bottom strand is the sensestrand and the top strand is the antisense strand, with 2′-O-methyl RNAmonomers located at alternating residues along the top strand, ratherthan the bottom strand presently depicted in the above schematic.

In a related embodiment, the DsiRNA comprises:

5′-[X1/D2]_(N)XXXXXXXXXXXXXXXXXXXXXXXX_(N*)Y-3′3′-[X2/D2]_(N)XXXXXXXXXXXXXXXXXXXXXXXX_(N*)-5′wherein “X”=RNA, “D”=DNA, “Y” is an optional overhang domain comprisedof 0-10 RNA monomers that are optionally 2′-O-methyl RNA monomers—incertain embodiments, “Y” is an overhang domain comprised of 1-4 RNAmonomers that are optionally 2′-O-methyl RNA monomers, and “N”=1 to 50or more, but is optionally 1-8 or 1-10, where at least one D1_(N) ispresent in the top strand and is base paired with a corresponding D2_(N)in the bottom strand. Optionally, D1_(N) and D1_(N+1) are base pairedwith corresponding D2_(N) and D2_(N+1); D1_(N), D1_(N+1) and D1_(N+2)are base paired with corresponding D2_(N), D1_(N+1) and D1_(N+2), etc.“N*”=0 to 15 or more, but is optionally 0, 1, 2, 3, 4, 5 or 6. In oneembodiment, the top strand is the sense strand, and the bottom strand isthe antisense strand. Alternatively, the bottom strand is the sensestrand and the top strand is the antisense strand, with 2′-O-methyl RNAmonomers located at alternating residues along the top strand, ratherthan the bottom strand presently depicted in the above schematic.

In another embodiment, the DNA:DNA-extended DsiRNA comprises strandshaving equal lengths possessing 1-3 mismatched residues that serve toorient Dicer cleavage (specifically, one or more of positions 1, 2 or 3on the first strand of the DsiRNA, when numbering from the 3′-terminalresidue, are mismatched with corresponding residues of the 5′-terminalregion on the second strand when first and second strands are annealedto one another). An exemplary DNA:DNA-extended DsiRNA agent with twoterminal mismatched residues is shown:

wherein “X”=RNA, “M”=Nucleic acid residues (RNA, DNA or non-natural ormodified nucleic acids) that do not base pair (hydrogen bond) withcorresponding “M” residues of otherwise complementary strand whenstrands are annealed, “D”=DNA and “N”=1 to 50 or more, but is optionally1-8 or 1-10. “N*”=0 to 15 or more, but is optionally 0, 1, 2, 3, 4, 5 or6. Any of the residues of such agents can optionally be 2′-O-methyl RNAmonomers—alternating positioning of 2′-O-methyl RNA monomers thatcommences from the 3′-terminal residue of the bottom (second) strand, asshown for above asymmetric agents, can also be used in the above“blunt/fray” DsiRNA agent. In one embodiment, the top strand (firststrand) is the sense strand, and the bottom strand (second strand) isthe antisense strand. Alternatively, the bottom strand is the sensestrand and the top strand is the antisense strand. Modification andDNA:DNA extension patterns paralleling those shown above forasymmetric/overhang agents can also be incorporated into such“blunt/frayed” agents.

In another embodiment, a length-extended DsiRNA agent is provided thatcomprises deoxyribonucleotides positioned at sites modeled to functionvia specific direction of Dicer cleavage, yet which does not require thepresence of a base-paired deoxyribonucleotide in the dsRNA structure.Exemplary structures for such a molecule are shown:

5′-XXDDXXXXXXXXXXXXXXXXXXXX_(N*)Y-3′ 3′-DDXXXXXXXXXXXXXXXXXXXXXX_(N*)-5′OR 5′-XDXDXXXXXXXXXXXXXXXXXXXX_(N*)Y-3′3′-DXDXXXXXXXXXXXXXXXXXXXXX_(N*)-5′wherein “X”=RNA, “Y” is an optional overhang domain comprised of 0-10RNA monomers that are optionally 2′-O-methyl RNA monomers—in certainembodiments, “Y” is an overhang domain comprised of 1-4 RNA monomersthat are optionally 2′-O-methyl RNA monomers, and “D”=DNA. “N*”=0 to 15or more, but is optionally 0, 1, 2, 3, 4, 5 or 6. In one embodiment, thetop strand is the sense strand, and the bottom strand is the antisensestrand. Alternatively, the bottom strand is the sense strand and the topstrand is the antisense strand.

In any of the above embodiments where the bottom strand of the abovestructure is the antisense strand, the positioning of twodeoxyribonucleotide residues at the ultimate and penultimate residues ofthe 5′ end of the antisense strand will help reduce off-target effects(as prior studies have shown a 2′-O-methyl modification of at least thepenultimate position from the 5′ terminus of the antisense strand toreduce off-target effects; see, e.g., US 2007/0223427).

In certain embodiments, the “D” residues of the above structures includeat least one PS-DNA or PS-RNA. Optionally, the “D” residues of the abovestructures include at least one modified nucleotide that inhibits Dicercleavage.

While the above-described “DNA-extended” DsiRNA agents can becategorized as either “left extended” or “right extended”, DsiRNA agentscomprising both left- and right-extended DNA-containing sequences withina single agent (e.g., both flanks surrounding a core dsRNA structure aredsDNA extensions) can also be generated and used in similar manner tothose described herein for “right-extended” and “left-extended” agents.

In some embodiments, the DsiRNA of the instant invention furthercomprises a linking moiety or domain that joins the sense and antisensestrands of a DNA:DNA-extended DsiRNA agent. Optionally, such a linkingmoiety domain joins the 3′ end of the sense strand and the 5′ end of theantisense strand. The linking moiety may be a chemical (non-nucleotide)linker, such as an oligomethylenediol linker, oligoethylene glycollinker, or other art-recognized linker moiety. Alternatively, the linkercan be a nucleotide linker, optionally including an extended loop and/ortetraloop.

In one embodiment, the DsiRNA agent has an asymmetric structure, withthe sense strand having a 25-base pair length, and the antisense strandhaving a 27-base pair length with a 1-4 base 3′-overhang (e.g., a onebase 3′-overhang, a two base 3′-overhang, a three base 3′-overhang or afour base 3′-overhang). In another embodiment, this DsiRNA agent has anasymmetric structure further containing 2 deoxynucleotides at the 3′ endof the sense strand.

In another embodiment, the DsiRNA agent has an asymmetric structure,with the antisense strand having a 25-base pair length, and the sensestrand having a 27-base pair length with a 1-4 base 3′-overhang (e.g., aone base 3′-overhang, a two base 3′-overhang, a three base 3′-overhangor a four base 3′-overhang). In another embodiment, this DsiRNA agenthas an asymmetric structure further containing 2 deoxyribonucleotides atthe 3′ end of the antisense strand.

Exemplary α-1 antitrypsin targeting DsiRNA agents of the invention, andtheir associated α-1 antitrypsin target sequences, include thefollowing, presented in the below series of tables:

Table Number:

(2) Selected Human Anti-α-1 antitrypsin DsiRNA Agents (Asymmetrics);(3) Selected Human Anti-α-1 antitrypsin DsiRNAs, Unmodified Duplexes(Asymmetrics);(4) DsiRNA Target Sequences (21mers) in α-1 antitrypsin mRNA;(5) Selected Human Anti-α-1 antitrypsin “Blunt/Blunt” DsiRNAs; and(6) DsiRNA Component 19 Nucleotide Target Sequences in α-1 antitrypsinmRNA(7) Additional Human Anti-α-1 antitrypsin DsiRNA Agents (Asymmetrics);(8) Additional Human Anti-α-1 antitrypsin DsiRNAs, Unmodified Duplexes(Asymmetrics);(9) Additional DsiRNA Target Sequences (21mers) in α-1 antitrypsin mRNA;(10) Additional Human Anti-α-1 antitrypsin “Blunt/Blunt” DsiRNAs; and(11) Additional DsiRNA Component 19 Nucleotide Target Sequences in α-1antitrypsin mRNA(12) Further Human Anti-α-1 antitrypsin DsiRNA Agents (Asymmetrics);(13) Further Human Anti-α-1 antitrypsin DsiRNAs, Unmodified Duplexes(Asymmetrics);(14) Further DsiRNA Target Sequences (21mers) in α-1 antitrypsin mRNA;(15) Further Human Anti-α-1 antitrypsin “Blunt/Blunt” DsiRNAs; and(16) Further DsiRNA Component 19 Nucleotide Target Sequences in α-1antitrypsin mRNA(17) Other Human Anti-α-1 antitrypsin DsiRNA Agents (Asymmetrics);(18) Other Human Anti-α-1 antitrypsin DsiRNAs, Unmodified Duplexes(Asymmetrics);(19) Other DsiRNA Target Sequences (21mers) in α-1 antitrypsin mRNA;(20) Other Human Anti-α-1 antitrypsin “Blunt/Blunt” DsiRNAs; and(21) Other DsiRNA Component 19 Nucleotide Target Sequences in α-1antitrypsin mRNA

TABLE 2 Selected Human Anti-α-1 antitrypsin DsiRNA Agents (Asymmetries)5′-CAUCCCACCAUGAUCAGGAUCACcc-3′ (SEQ ID NO: 1)3′-AUGUAGGGUGGUACUAGUCCUAGUGGG-5′ (SEQ ID NO: 199) AAT-395 Target:5′-TACATCCCACCATGATCAGGATCACCC-3′ (SEQ ID NO: 397)5′-CAGCUGGCACACCAGUCCAACAGca-3′ (SEQ ID NO: 2)3′-CGGUCGACCGUGUGGUCAGGUUGUCGU-5′ (SEQ ID NO: 200) AAT-475 Target:5′-GCCAGCTGGCACACCAGTCCAACAGCA-3′ (SEQ ID NO: 398)5′-GCUGGCACACCAGUCCAACAGCAcc-3′ (SEQ ID NO: 3)3′-GUCGACCGUGUGGUCAGGUUGUCGUGG-5′ (SEQ ID NO: 201) AAT-477 Target:5′-CAGCTGGCACACCAGTCCAACAGCACC-3′ (SEQ ID NO: 399)5′-GGCACACCAGUCCAACAGCACCAat-3′ (SEQ ID NO: 4)3′-GACCGUGUGGUCAGGUUGUCGUGGUUA-5′ (SEQ ID NO: 202) AAT-480 Target:5′-CTGGCACACCAGTCCAACAGCACCAAT-3′ (SEQ ID NO: 400)5′-GCACACCAGUCCAACAGCACCAAta-3′ (SEQ ID NO: 5)3′-ACCGUGUGGUCAGGUUGUCGUGGUUAU-5′ (SEQ ID NO: 203) AAT-481 Target:5′-TGGCACACCAGTCCAACAGCACCAATA-3′ (SEQ ID NO: 401)5′-CACACCAGUCCAACAGCACCAAUat-3′ (SEQ ID NO: 6)3′-CCGUGUGGUCAGGUUGUCGUGGUUAUA-5′ (SEQ ID NO: 204) AAT-482 Target:5′-GGCACACCAGTCCAACAGCACCAATAT-3′ (SEQ ID NO: 402)5′-ACACCAGUCCAACAGCACCAAUAtc-3′ (SEQ ID NO: 7)3′-CGUGUGGUCAGGUUGUCGUGGUUAUAG-5′ (SEQ ID NO: 205) AAT-483 Target:5′-GCACACCAGTCCAACAGCACCAATATC-3′ (SEQ ID NO: 403)5′-CACCAGUCCAACAGCACCAAUAUct-3′ (SEQ ID NO: 8)3′-GUGUGGUCAGGUUGUCGUGGUUAUAGA-5′ (SEQ ID NO: 206) AAT-484 Target:5′-CACACCAGTCCAACAGCACCAATATCT-3′ (SEQ ID NO: 404)5′-CCAAUAUCUUCUUCUCCCCAGUGag-3′ (SEQ ID NO: 9)3′-GUGGUUAUAGAAGAAGAGGGGUCACUC-5′ (SEQ ID NO: 207) AAT-500 Target:5′-CACCAATATCTTCTTCTCCCCAGTGAG-3′ (SEQ ID NO: 405)5′-CAAUAUCUUCUUCUCCCCAGUGAgC-3′ (SEQ ID NO: 10)3′-UGGUUAUAGAAGAAGAGGGGUCACUCG-5′ (SEQ ID NO: 208) AAT-501 Target:5′-ACCAATATCTTCTTCTCCCCAGTGAGC-3′ (SEQ ID NO: 406)5′-AAUAUCUUCUUCUCCCCAGUGAGca-3′ (SEQ ID NO: 11)3′-GGUUAUAGAAGAAGAGGGGUCACUCGU-5′ (SEQ ID NO: 209) AAT-502 Target:5′-CCAATATCTTCTTCTCCCCAGTGAGCA-3′ (SEQ ID NO: 407)5′-AUAUCUUCUUCUCCCCAGUGAGCat-3′ (SEQ ID NO: 12)3′-GUUAUAGAAGAAGAGGGGUCACUCGUA-5′ (SEQ ID NO: 210) AAT-503 Target:5′-CAATATCTTCTTCTCCCCAGTGAGCAT-3′ (SEQ ID NO: 408)5′-UAUCUUCUUCUCCCCAGUGAGCAtC-3′ (SEQ ID NO: 13)3′-UUAUAGAAGAAGAGGGGUCACUCGUAG-5′ (SEQ ID NO: 211) AAT-504 Target:5′-AATATCTTCTTCTCCCCAGTGAGCATC-3′ (SEQ ID NO: 409)5′-AUCUUCUUCUCCCCAGUGAGCAUcg-3′ (SEQ ID NO: 14)3′-UAUAGAAGAAGAGGGGUCACUCGUAGC-5′ (SEQ ID NO: 212) AAT-505 Target:5′-ATATCTTCTTCTCCCCAGTGAGCATCG-3′ (SEQ ID NO: 410)5′-UCUUCUUCUCCCCAGUGAGCAUCgc-3′ (SEQ ID NO: 15)3′-AUAGAAGAAGAGGGGUCACUCGUAGCG-5′ (SEQ ID NO: 213) AAT-506 Target:5′-TATCTTCTTCTCCCCAGTGAGCATCGC-3′ (SEQ ID NO: 411)5′-CUUCUUCUCCCCAGUGAGCAUCGct-3′ (SEQ ID NO: 16)3′-UAGAAGAAGAGGGGUCACUCGUAGCGA-5′ (SEQ ID NO: 214) AAT-507 Target:5′-ATCTTCTTCTCCCCAGTGAGCATCGCT-3′ (SEQ ID NO: 412)5′-UUCUUCUCCCCAGUGAGCAUCGCta-3′ (SEQ ID NO: 17)3′-AGAAGAAGAGGGGUCACUCGUAGCGAU-5′ (SEQ ID NO: 215) AAT-508 Target:5′-TCTTCTTCTCCCCAGTGAGCATCGCTA-3′ (SEQ ID NO: 413)5′-UCUUCUCCCCAGUGAGCAUCGCUac-3′ (SEQ ID NO: 18)3′-GAAGAAGAGGGGUCACUCGUAGCGAUG-5′ (SEQ ID NO: 216) AAT-509 Target:5′-CTTCTTCTCCCCAGTGAGCATCGCTAC-3′ (SEQ ID NO: 414)5′-CUUCUCCCCAGUGAGCAUCGCUAca-3′ (SEQ ID NO: 19)3′-AAGAAGAGGGGUCACUCGUAGCGAUGU-5′ (SEQ ID NO: 217) AAT-510 Target:5′-TTCTTCTCCCCAGTGAGCATCGCTACA-3′ (SEQ ID NO: 415)5′-UCUCCCCAGUGAGCAUCGCUACAgc-3′ (SEQ ID NO: 20)3′-GAAGAGGGGUCACUCGUAGCGAUGUCG-5′ (SEQ ID NO: 218) AAT-512 Target:5′-CTTCTCCCCAGTGAGCATCGCTACAGC-3′ (SEQ ID NO: 416)5′-CUCCCCAGUGAGCAUCGCUACAGcc-3′ (SEQ ID NO: 21)3′-AAGAGGGGUCACUCGUAGCGAUGUCGG-5′ (SEQ ID NO: 219) AAT-513 Target:5′-TTCTCCCCAGTGAGCATCGCTACAGCC-3′ (SEQ ID NO: 417)5′-CCCCAGUGAGCAUCGCUACAGCCtt-3′ (SEQ ID NO: 22)3′-GAGGGGUCACUCGUAGCGAUGUCGGAA-5′ (SEQ ID NO: 220) AAT-515 Target:5′-CTCCCCAGTGAGCATCGCTACAGCCTT-3′ (SEQ ID NO: 418)5′-ACAGCCUUUGCAAUGCUCUCCCUgg-3′ (SEQ ID NO: 23)3′-GAUGUCGGAAACGUUACGAGAGGGACC-5′ (SEQ ID NO: 221) AAT-532 Target:5′-CTACAGCCTTTGCAATGCTCTCCCTGG-3′ (SEQ ID NO: 419)5′-UGCAAUGCUCUCCCUGGGGACCAag-3′ (SEQ ID NO: 24)3′-AAACGUUACGAGAGGGACCCCUGGUUC-5′ (SEQ ID NO: 222) AAT-540 Target:5′-TTTGCAATGCTCTCCCTGGGGACCAAG-3′ (SEQ ID NO: 420)5′-AAAUCCUGGAGGGCCUGAAUUUCaa-3′ (SEQ ID NO: 25)3′-ACUUUAGGACCUCCCGGACUUAAAGUU-5′ (SEQ ID NO: 223) AAT-581 Target:5′-TGAAATCCTGGAGGGCCTGAATTTCAA-3′ (SEQ ID NO: 421)5′-AAUCCUGGAGGGCCUGAAUUUCAac-3′ (SEQ ID NO: 26)3′-CUUUAGGACCUCCCGGACUUAAAGUUG-5′ (SEQ ID NO: 224) AAT-582 Target:5′-GAAATCCTGGAGGGCCTGAATTTCAAC-3′ (SEQ ID NO: 422)5′-AUCCUGGAGGGCCUGAAUUUCAAcc-3′ (SEQ ID NO: 27)3′-UUUAGGACCUCCCGGACUUAAAGUUGG-5′ (SEQ ID NO: 225) AAT-583 Target:5′-AAATCCTGGAGGGCCTGAATTTCAACC-3′ (SEQ ID NO: 423)5′-CCUGGAGGGCCUGAAUUUCAACCtc-3′ (SEQ ID NO: 28)3′-UAGGACCUCCCGGACUUAAAGUUGGAG-5′ (SEQ ID NO: 226) AAT-585 Target:5′-ATCCTGGAGGGCCTGAATTTCAACCTC-3′ (SEQ ID NO: 424)5′-CUGGAGGGCCUGAAUUUCAACCUca-3′ (SEQ ID NO: 29)3′-AGGACCUCCCGGACUUAAAGUUGGAGU-5′ (SEQ ID NO: 227) AAT-586 Target:5′-TCCTGGAGGGCCTGAATTTCAACCTCA-3′ (SEQ ID NO: 425)5′-UGGAGGGCCUGAAUUUCAACCUCac-3′ (SEQ ID NO: 30)3′-GGACCUCCCGGACUUAAAGUUGGAGUG-5′ (SEQ ID NO: 228) AAT-587 Target:5′-CCTGGAGGGCCTGAATTTCAACCTCAC-3′ (SEQ ID NO: 426)5′-CAUGAAGGCUUCCAGGAACUCCUcc-3′ (SEQ ID NO: 31)3′-AGGUACUUCCGAAGGUCCUUGAGGAGG-5′ (SEQ ID NO: 229) AAT-634 Target:5′-TCCATGAAGGCTTCCAGGAACTCCTCC-3′ (SEQ ID NO: 427)5′-GAAGGCUUCCAGGAACUCCUCCGta-3′ (SEQ ID NO: 32)3′-UACUUCCGAAGGUCCUUGAGGAGGCAU-5′ (SEQ ID NO: 230) AAT-637 Target:5′-ATGAAGGCTTCCAGGAACTCCTCCGTA-3′ (SEQ ID NO: 428)5′-AAGGCUUCCAGGAACUCCUCCGUac-3′ (SEQ ID NO: 33)3′-ACUUCCGAAGGUCCUUGAGGAGGCAUG-5′ (SEQ ID NO: 231) AAT-638 Target:5′-TGAAGGCTTCCAGGAACTCCTCCGTAC-3′ (SEQ ID NO: 429)5′-AGCCAGACAGCCAGCUCCAGCUGac-3′ (SEQ ID NO: 34)3′-GGUCGGUCUGUCGGUCGAGGUCGACUG-5′ (SEQ ID NO: 232) AAT-671 Target:5′-CCAGCCAGACAGCCAGCTCCAGCTGAC-3′ (SEQ ID NO: 430)5′-CCAGACAGCCAGCUCCAGCUGACca-3′ (SEQ ID NO: 35)3′-UCGGUCUGUCGGUCGAGGUCGACUGGU-5′ (SEQ ID NO: 233) AAT-673 Target:5′-AGCCAGACAGCCAGCTCCAGCTGACCA-3′ (SEQ ID NO: 431)5′-AGACAGCCAGCUCCAGCUGACCAcc-3′ (SEQ ID NO: 36)3′-GGUCUGUCGGUCGAGGUCGACUGGUGG-5′ (SEQ ID NO: 234) AAT-675 Target:5′-CCAGACAGCCAGCTCCAGCTGACCACC-3′ (SEQ ID NO: 432)5′-GACAGCCAGCUCCAGCUGACCACcg-3′ (SEQ ID NO: 37)3′-GUCUGUCGGUCGAGGUCGACUGGUGGC-5′ (SEQ ID NO: 235) AAT-676 Target:5′-CAGACAGCCAGCTCCAGCTGACCACCG-3′ (SEQ ID NO: 433)5′-UAGUGGAUAAGUUUUUGGAGGAUgt-3′ (SEQ ID NO: 38)3′-CGAUCACCUAUUCAAAAACCUCCUACA-5′ (SEQ ID NO: 236) AAT-734 Target:5′-GCTAGTGGATAAGTTTTTGGAGGATGT-3′ (SEQ ID NO: 434)5′-AGUGGAUAAGUUUUUGGAGGAUGtt-3′ (SEQ ID NO: 39)3′-GAUCACCUAUUCAAAAACCUCCUACAA-5′ (SEQ ID NO: 237) AAT-735 Target:5′-CTAGTGGATAAGTTTTTGGAGGATGTT-3′ (SEQ ID NO: 435)5′-GUGGAUAAGUUUUUGGAGGAUGUta-3′ (SEQ ID NO: 40)3′-AUCACCUAUUCAAAAACCUCCUACAAU-5′ (SEQ ID NO: 238) AAT-736 Target:5′-TAGTGGATAAGTTTTTGGAGGATGTTA-3′ (SEQ ID NO: 436)5′-UGGAUAAGUUUUUGGAGGAUGUUaa-3′ (SEQ ID NO: 41)3′-UCACCUAUUCAAAAACCUCCUACAAUU-5′ (SEQ ID NO: 239) AAT-737 Target:5′-AGTGGATAAGTTTTTGGAGGATGTTAA-3′ (SEQ ID NO: 437)5′-GGAUAAGUUUUUGGAGGAUGUUAaa-3′ (SEQ ID NO: 42)3′-CACCUAUUCAAAAACCUCCUACAAUUU-5′ (SEQ ID NO: 240) AAT-738 Target:5′-GTGGATAAGTTTTTGGAGGATGTTAAA-3′ (SEQ ID NO: 438)5′-GAUAAGUUUUUGGAGGAUGUUAAaa-3′ (SEQ ID NO: 43)3′-ACCUAUUCAAAAACCUCCUACAAUUUU-5′ (SEQ ID NO: 241) AAT-739 Target:5′-TGGATAAGTTTTTGGAGGATGTTAAAA-3′ (SEQ ID NO: 439)5′-AUAAGUUUUUGGAGGAUGUUAAAaa-3′ (SEQ ID NO: 44)3′-CCUAUUCAAAAACCUCCUACAAUUUUU-5′ (SEQ ID NO: 242) AAT-740 Target:5′-GGATAAGTTTTTGGAGGATGTTAAAAA-3′ (SEQ ID NO: 440)5′-UGUACCACUCAGAAGCCUUCACUgt-3′ (SEQ ID NO: 45)3′-CAACAUGGUGAGUCUUCGGAAGUGACA-5′ (SEQ ID NO: 243) AAT-767 Target:5′-GTTGTACCACTCAGAAGCCTTCACTGT-3′ (SEQ ID NO: 441)5′-GUACCACUCAGAAGCCUUCACUGtC-3′ (SEQ ID NO: 46)3′-AACAUGGUGAGUCUUCGGAAGUGACAG-5′ (SEQ ID NO: 244) AAT-768 Target:5′-TTGTACCACTCAGAAGCCTTCACTGTC-3′ (SEQ ID NO: 442)5′-ACUCAAGGGAAAAUUGUGGAUUUgg-3′ (SEQ ID NO: 47)3′-CAUGAGUUCCCUUUUAACACCUAAACC-5′ (SEQ ID NO: 245) AAT-850 Target:5′-GTACTCAAGGGAAAATTGTGGATTTGG-3′ (SEQ ID NO: 443)5′-CUCAAGGGAAAAUUGUGGAUUUGgt-3′ (SEQ ID NO: 48)3′-AUGAGUUCCCUUUUAACACCUAAACCA-5′ (SEQ ID NO: 246) AAT-851 Target:5′-TACTCAAGGGAAAATTGTGGATTTGGT-3′ (SEQ ID NO: 444)5′-UCAAGGGAAAAUUGUGGAUUUGGtc-3′ (SEQ ID NO: 49)3′-UGAGUUCCCUUUUAACACCUAAACCAG-5′ (SEQ ID NO: 247) AAT-852 Target:5′-ACTCAAGGGAAAATTGTGGATTTGGTC-3′ (SEQ ID NO: 445)5′-CAAGGGAAAAUUGUGGAUUUGGUca-3′ (SEQ ID NO: 50)3′-GAGUUCCCUUUUAACACCUAAACCAGU-5′ (SEQ ID NO: 248) AAT-853 Target:5′-CTCAAGGGAAAATTGTGGATTTGGTCA-3′ (SEQ ID NO: 446)5′-AAGGGAAAAUUGUGGAUUUGGUCaa-3′ (SEQ ID NO: 51)3′-AGUUCCCUUUUAACACCUAAACCAGUU-5′ (SEQ ID NO: 249) AAT-854 Target:5′-TCAAGGGAAAATTGTGGATTTGGTCAA-3′ (SEQ ID NO: 447)5′-AGGGAAAAUUGUGGAUUUGGUCAag-3′ (SEQ ID NO: 52)3′-GUUCCCUUUUAACACCUAAACCAGUUC-5′ (SEQ ID NO: 250) AAT-855 Target:5′-CAAGGGAAAATTGTGGATTTGGTCAAG-3′ (SEQ ID NO: 448)5′-GGGAAAAUUGUGGAUUUGGUCAAgg-3′ (SEQ ID NO: 53)3′-UUCCCUUUUAACACCUAAACCAGUUCC-5′ (SEQ ID NO: 251) AAT-856 Target:5′-AAGGGAAAATTGTGGATTTGGTCAAGG-3′ (SEQ ID NO: 449)5′-GGAAAAUUGUGGAUUUGGUCAAGga-3′ (SEQ ID NO: 54)3′-UCCCUUUUAACACCUAAACCAGUUCCU-5′ (SEQ ID NO: 252) AAT-857 Target:5′-AGGGAAAATTGTGGATTTGGTCAAGGA-3′ (SEQ ID NO: 450)5′-GAAAAUUGUGGAUUUGGUCAAGGag-3′ (SEQ ID NO: 55)3′-CCCUUUUAACACCUAAACCAGUUCCUC-5′ (SEQ ID NO: 253) AAT-858 Target:5′-GGGAAAATTGTGGATTTGGTCAAGGAG-3′ (SEQ ID NO: 451)5′-AAAAUUGUGGAUUUGGUCAAGGAgc-3′ (SEQ ID NO: 56)3′-CCUUUUAACACCUAAACCAGUUCCUCG-5′ (SEQ ID NO: 254) AAT-859 Target:5′-GGAAAATTGTGGATTTGGTCAAGGAGC-3′ (SEQ ID NO: 452)5′-AAAUUGUGGAUUUGGUCAAGGAGct-3′ (SEQ ID NO: 57)3′-CUUUUAACACCUAAACCAGUUCCUCGA-5′ (SEQ ID NO: 255) AAT-860 Target:5′-GAAAATTGTGGATTTGGTCAAGGAGCT-3′ (SEQ ID NO: 453)5′-AAUUGUGGAUUUGGUCAAGGAGCtt-3′ (SEQ ID NO: 58)3′-UUUUAACACCUAAACCAGUUCCUCGAA-5′ (SEQ ID NO: 256) AAT-861 Target:5′-AAAATTGTGGATTTGGTCAAGGAGCTT-3′ (SEQ ID NO: 454)5′-AUUGUGGAUUUGGUCAAGGAGCUtg-3′ (SEQ ID NO: 59)3′-UUUAACACCUAAACCAGUUCCUCGAAC-5′ (SEQ ID NO: 257) AAT-862 Target:5′-AAATTGTGGATTTGGTCAAGGAGCTTG-3′ (SEQ ID NO: 455)5′-UUGUGGAUUUGGUCAAGGAGCUUga-3′ (SEQ ID NO: 60)3′-UUAACACCUAAACCAGUUCCUCGAACU-5′ (SEQ ID NO: 258) AAT-863 Target:5′-AATTGTGGATTTGGTCAAGGAGCTTGA-3′ (SEQ ID NO: 456)5′-UGUGGAUUUGGUCAAGGAGCUUGac-3′ (SEQ ID NO: 61)3′-UAACACCUAAACCAGUUCCUCGAACUG-5′ (SEQ ID NO: 259) AAT-864 Target:5′-ATTGTGGATTTGGTCAAGGAGCTTGAC-3′ (SEQ ID NO: 457)5′-GUGGAUUUGGUCAAGGAGCUUGAca-3′ (SEQ ID NO: 62)3′-AACACCUAAACCAGUUCCUCGAACUGU-5′ (SEQ ID NO: 260) AAT-865 Target:5′-TTGTGGATTTGGTCAAGGAGCTTGACA-3′ (SEQ ID NO: 458)5′-UGGAUUUGGUCAAGGAGCUUGACag-3′ (SEQ ID NO: 63)3′-ACACCUAAACCAGUUCCUCGAACUGUC-5′ (SEQ ID NO: 261) AAT-866 Target:5′-TGTGGATTTGGTCAAGGAGCTTGACAG-3′ (SEQ ID NO: 459)5′-GGAUUUGGUCAAGGAGCUUGACAga-3′ (SEQ ID NO: 64)3′-CACCUAAACCAGUUCCUCGAACUGUCU-5′ (SEQ ID NO: 262) AAT-867 Target:5′-GTGGATTTGGTCAAGGAGCTTGACAGA-3′ (SEQ ID NO: 460)5′-GAUUUGGUCAAGGAGCUUGACAGag-3′ (SEQ ID NO: 65)3′-ACCUAAACCAGUUCCUCGAACUGUCUC-5′ (SEQ ID NO: 263) AAT-868 Target:5′-TGGATTTGGTCAAGGAGCTTGACAGAG-3′ (SEQ ID NO: 461)5′-AUUUGGUCAAGGAGCUUGACAGAga-3′ (SEQ ID NO: 66)3′-CCUAAACCAGUUCCUCGAACUGUCUCU-5′ (SEQ ID NO: 264) AAT-869 Target:5′-GGATTTGGTCAAGGAGCTTGACAGAGA-3′ (SEQ ID NO: 462)5′-UUUGGUCAAGGAGCUUGACAGAGac-3′ (SEQ ID NO: 67)3′-CUAAACCAGUUCCUCGAACUGUCUCUG-5′ (SEQ ID NO: 265) AAT-870 Target:5′-GATTTGGTCAAGGAGCTTGACAGAGAC-3′ (SEQ ID NO: 463)5′-UUGGUCAAGGAGCUUGACAGAGAca-3′ (SEQ ID NO: 68)3′-UAAACCAGUUCCUCGAACUGUCUCUGU-5′ (SEQ ID NO: 266) AAT-871 Target:5′-ATTTGGTCAAGGAGCTTGACAGAGACA-3′ (SEQ ID NO: 464)5′-UGGUCAAGGAGCUUGACAGAGACac-3′ (SEQ ID NO: 69)3′-AAACCAGUUCCUCGAACUGUCUCUGUG-5′ (SEQ ID NO: 267) AAT-872 Target:5′-TTTGGTCAAGGAGCTTGACAGAGACAC-3′ (SEQ ID NO: 465)5′-CAGUUUUUGCUCUGGUGAAUUACat-3′ (SEQ ID NO: 70)3′-GUGUCAAAAACGAGACCACUUAAUGUA-5′ (SEQ ID NO: 268) AAT-896 Target:5′-CACAGTTTTTGCTCTGGTGAATTACAT-3′ (SEQ ID NO: 466)5′-AGUUUUUGCUCUGGUGAAUUACAtc-3′ (SEQ ID NO: 71)3′-UGUCAAAAACGAGACCACUUAAUGUAG-5′ (SEQ ID NO: 269) AAT-897 Target:5′-ACAGTTTTTGCTCTGGTGAATTACATC-3′ (SEQ ID NO: 467)5′-GUUUUUGCUCUGGUGAAUUACAUct-3′ (SEQ ID NO: 72)3′-GUCAAAAACGAGACCACUUAAUGUAGA-5′ (SEQ ID NO: 270) AAT-898 Target:5′-CAGTTTTTGCTCTGGTGAATTACATCT-3′ (SEQ ID NO: 468)5′-UUUUUGCUCUGGUGAAUUACAUCtt-3′ (SEQ ID NO: 73)3′-UCAAAAACGAGACCACUUAAUGUAGAA-5′ (SEQ ID NO: 271) AAT-899 Target:5′-AGTTTTTGCTCTGGTGAATTACATCTT-3′ (SEQ ID NO: 469)5′-AAAGGCAAAUGGGAGAGACCCUUtg-3′ (SEQ ID NO: 74)3′-AAUUUCCGUUUACCCUCUCUGGGAAAC-5′ (SEQ ID NO: 272) AAT-928 Target:5′-TTAAAGGCAAATGGGAGAGACCCTTTG-3′ (SEQ ID NO: 470)5′-AAGGCAAAUGGGAGAGACCCUUUga-3′ (SEQ ID NO: 75)3′-AUUUCCGUUUACCCUCUCUGGGAAACU-5′ (SEQ ID NO: 273) AAT-929 Target:5′-TAAAGGCAAATGGGAGAGACCCTTTGA-3′ (SEQ ID NO: 471)5′-AGGCAAAUGGGAGAGACCCUUUGaa-3′ (SEQ ID NO: 76)3′-UUUCCGUUUACCCUCUCUGGGAAACUU-5′ (SEQ ID NO: 274) AAT-930 Target:5′-AAAGGCAAATGGGAGAGACCCTTTGAA-3′ (SEQ ID NO: 472)5′-GGCAAAUGGGAGAGACCCUUUGAag-3′ (SEQ ID NO: 77)3′-UUCCGUUUACCCUCUCUGGGAAACUUC-5′ (SEQ ID NO: 275) AAT-931 Target:5′-AAGGCAAATGGGAGAGACCCTTTGAAG-3′ (SEQ ID NO: 473)5′-AGGAAGAGGACUUCCACGUGGACca-3′ (SEQ ID NO: 78)3′-GCUCCUUCUCCUGAAGGUGCACCUGGU-5′ (SEQ ID NO: 276) AAT-968 Target:5′-CGAGGAAGAGGACTTCCACGTGGACCA-3′ (SEQ ID NO: 474)5′-GGAAGAGGACUUCCACGUGGACCag-3′ (SEQ ID NO: 79)3′-CUCCUUCUCCUGAAGGUGCACCUGGUC-5′ (SEQ ID NO: 277) AAT-969 Target:5′-GAGGAAGAGGACTTCCACGTGGACCAG-3′ (SEQ ID NO: 475)5′-GAAGAGGACUUCCACGUGGACCAgg-3′ (SEQ ID NO: 80)3′-UCCUUCUCCUGAAGGUGCACCUGGUCC-5′ (SEQ ID NO: 278) AAT-970 Target:5′-AGGAAGAGGACTTCCACGTGGACCAGG-3′ (SEQ ID NO: 476)5′-AAGAGGACUUCCACGUGGACCAGgt-3′ (SEQ ID NO: 81)3′-CCUUCUCCUGAAGGUGCACCUGGUCCA-5′ (SEQ ID NO: 279) AAT-971 Target:5′-GGAAGAGGACTTCCACGTGGACCAGGT-3′ (SEQ ID NO: 477)5′-GAGGACUUCCACGUGGACCAGGUga-3′ (SEQ ID NO: 82)3′-UUCUCCUGAAGGUGCACCUGGUCCACU-5′ (SEQ ID NO: 280) AAT-973 Target:5′-AAGAGGACTTCCACGTGGACCAGGTGA-3′ (SEQ ID NO: 478)5′-AGGACUUCCACGUGGACCAGGUGac-3′ (SEQ ID NO: 83)3′-UCUCCUGAAGGUGCACCUGGUCCACUG-5′ (SEQ ID NO: 281) AAT-974 Target:5′-AGAGGACTTCCACGTGGACCAGGTGAC-3′ (SEQ ID NO: 479)5′-GACUUCCACGUGGACCAGGUGACca-3′ (SEQ ID NO: 84)3′-UCCUGAAGGUGCACCUGGUCCACUGGU-5′ (SEQ ID NO: 282) AAT-976 Target:5′-AGGACTTCCACGTGGACCAGGTGACCA-3′ (SEQ ID NO: 480)5′-GUUUAGGCAUGUUUAACAUCCAGca-3′ (SEQ ID NO: 85)3′-CGCAAAUCCGUACAAAUUGUAGGUCGU-5′ (SEQ ID NO: 283) AAT-1025 Target:5′-GCGTTTAGGCATGTTTAACATCCAGCA-3′ (SEQ ID NO: 481)5′-UUUAGGCAUGUUUAACAUCCAGCac-3′ (SEQ ID NO: 86)3′-GCAAAUCCGUACAAAUUGUAGGUCGUG-5′ (SEQ ID NO: 284) AAT-1026 Target:5′-CGTTTAGGCATGTTTAACATCCAGCAC-3′ (SEQ ID NO: 482)5′-GCUGUCCAGCUGGGUGCUGCUGAtg-3′ (SEQ ID NO: 87)3′-UUCGACAGGUCGACCCACGACGACUAC-5′ (SEQ ID NO: 285) AAT-1059 Target:5′-AAGCTGTCCAGCTGGGTGCTGCTGATG-3′ (SEQ ID NO: 483)5′-CUGUCCAGCUGGGUGCUGCUGAUga-3′ (SEQ ID NO: 88)3′-UCGACAGGUCGACCCACGACGACUACU-5′ (SEQ ID NO: 286) AAT-1060 Target:5′-AGCTGTCCAGCTGGGTGCTGCTGATGA-3′ (SEQ ID NO: 484)5′-CAAUGCCACCGCCAUCUUCUUCCtg-3′ (SEQ ID NO: 89)3′-CCGUUACGGUGGCGGUAGAAGAAGGAC-5′ (SEQ ID NO: 287) AAT-1095 Target:5′-GGCAATGCCACCGCCATCTTCTTCCTG-3′ (SEQ ID NO: 485)5′-AAUGCCACCGCCAUCUUCUUCCUgc-3′ (SEQ ID NO: 90)3′-CGUUACGGUGGCGGUAGAAGAAGGACG-5′ (SEQ ID NO: 288) AAT-1096 Target:5′-GCAATGCCACCGCCATCTTCTTCCTGC-3′ (SEQ ID NO: 486)5′-CCACCGCCAUCUUCUUCCUGCCUga-3′ (SEQ ID NO: 91)3′-ACGGUGGCGGUAGAAGAAGGACGGACU-5′ (SEQ ID NO: 289) AAT-1100 Target:5′-TGCCACCGCCATCTTCTTCCTGCCTGA-3′ (SEQ ID NO: 487)5′-CACCGCCAUCUUCUUCCUGCCUGat-3′ (SEQ ID NO: 92)3′-CGGUGGCGGUAGAAGAAGGACGGACUA-5′ (SEQ ID NO: 290) AAT-1101 Target:5′-GCCACCGCCATCTTCTTCCTGCCTGAT-3′ (SEQ ID NO: 488)5′-ACCGCCAUCUUCUUCCUGCCUGAtg-3′ (SEQ ID NO: 93)3′-GGUGGCGGUAGAAGAAGGACGGACUAC-5′ (SEQ ID NO: 291) AAT-1102 Target:5′-CCACCGCCATCTTCTTCCTGCCTGATG-3′ (SEQ ID NO: 489)5′-CCGCCAUCUUCUUCCUGCCUGAUga-3′ (SEQ ID NO: 94)3′-GUGGCGGUAGAAGAAGGACGGACUACU-5′ (SEQ ID NO: 292) AAT-1103 Target:5′-CACCGCCATCTTCTTCCTGCCTGATGA-3′ (SEQ ID NO: 490)5′-CGCCAUCUUCUUCCUGCCUGAUGag-3′ (SEQ ID NO: 95)3′-UGGCGGUAGAAGAAGGACGGACUACUC-5′ (SEQ ID NO: 293) AAT-1104 Target:5′-ACCGCCATCTTCTTCCTGCCTGATGAG-3′ (SEQ ID NO: 491)5′-GCCAUCUUCUUCCUGCCUGAUGAgg-3′ (SEQ ID NO: 96)3′-GGCGGUAGAAGAAGGACGGACUACUCC-5′ (SEQ ID NO: 294) AAT-1105 Target:5′-CCGCCATCTTCTTCCTGCCTGATGAGG-3′ (SEQ ID NO: 492)5′-AUCUUCUUCCUGCCUGAUGAGGGga-3′ (SEQ ID NO: 97)3′-GGUAGAAGAAGGACGGACUACUCCCCU-5′ (SEQ ID NO: 295) AAT-1108 Target:5′-CCATCTTCTTCCTGCCTGATGAGGGGA-3′ (SEQ ID NO: 493)5′-CUUCCUGCCUGAUGAGGGGAAACta-3′ (SEQ ID NO: 98)3′-AAGAAGGACGGACUACUCCCCUUUGAU-5′ (SEQ ID NO: 296) AAT-1113 Target:5′-TTCTTCCTGCCTGATGAGGGGAAACTA-3′ (SEQ ID NO: 494)5′-UUCCUGCCUGAUGAGGGGAAACUac-3′ (SEQ ID NO: 99)3′-AGAAGGACGGACUACUCCCCUUUGAUG-5′ (SEQ ID NO: 297) AAT-1114 Target:5′-TCTTCCTGCCTGATGAGGGGAAACTAC-3′ (SEQ ID NO: 495)5′-UCCUGCCUGAUGAGGGGAAACUAca-3′ (SEQ ID NO: 100)3′-GAAGGACGGACUACUCCCCUUUGAUGU-5′ (SEQ ID NO: 298) AAT-1115 Target:5′-CTTCCTGCCTGATGAGGGGAAACTACA-3′ (SEQ ID NO: 496)5′-CCUGCCUGAUGAGGGGAAACUACag-3′ (SEQ ID NO: 101)3′-AAGGACGGACUACUCCCCUUUGAUGUC-5′ (SEQ ID NO: 299) AAT-1116 Target:5′-TTCCTGCCTGATGAGGGGAAACTACAG-3′ (SEQ ID NO: 497)5′-CUGCCUGAUGAGGGGAAACUACAgc-3′ (SEQ ID NO: 102)3′-AGGACGGACUACUCCCCUUUGAUGUCG-5′ (SEQ ID NO: 300) AAT-1117 Target:5′-TCCTGCCTGATGAGGGGAAACTACAGC-3′ (SEQ ID NO: 498)5′-UGCCUGAUGAGGGGAAACUACAGca-3′ (SEQ ID NO: 103)3′-GGACGGACUACUCCCCUUUGAUGUCGU-5′ (SEQ ID NO: 301) AAT-1118 Target:5′-CCTGCCTGATGAGGGGAAACTACAGCA-3′ (SEQ ID NO: 499)5′-AGCACCUGGAAAAUGAACUCACCca-3′ (SEQ ID NO: 104)3′-UGUCGUGGACCUUUUACUUGAGUGGGU-5′ (SEQ ID NO: 302) AAT-1139 Target:5′-ACAGCACCTGGAAAATGAACTCACCCA-3′ (SEQ ID NO: 500)5′-GCACCUGGAAAAUGAACUCACCCac-3′ (SEQ ID NO: 105)3′-GUCGUGGACCUUUUACUUGAGUGGGUG-5′ (SEQ ID NO: 303) AAT-1140 Target:5′-CAGCACCTGGAAAATGAACTCACCCAC-3′ (SEQ ID NO: 501)5′-CACCUGGAAAAUGAACUCACCCAcg-3′ (SEQ ID NO: 106)3′-UCGUGGACCUUUUACUUGAGUGGGUGC-5′ (SEQ ID NO: 304) AAT-1141 Target:5′-AGCACCTGGAAAATGAACTCACCCACG-3′ (SEQ ID NO: 502)5′-ACCUGGAAAAUGAACUCACCCACga-3′ (SEQ ID NO: 107)3′-CGUGGACCUUUUACUUGAGUGGGUGCU-5′ (SEQ ID NO: 305) AAT-1142 Target:5′-GCACCTGGAAAATGAACTCACCCACGA-3′ (SEQ ID NO: 503)5′-CCUGGAAAAUGAACUCACCCACGat-3′ (SEQ ID NO: 108)3′-GUGGACCUUUUACUUGAGUGGGUGCUA-5′ (SEQ ID NO: 306) AAT-1143 Target:5′-CACCTGGAAAATGAACTCACCCACGAT-3′ (SEQ ID NO: 504)5′-AUAUCAUCACCAAGUUCCUGGAAaa-3′ (SEQ ID NO: 109)3′-GCUAUAGUAGUGGUUCAAGGACCUUUU-5′ (SEQ ID NO: 307) AAT-1166 Target:5′-CGATATCATCACCAAGTTCCTGGAAAA-3′ (SEQ ID NO: 505)5′-UAUCAUCACCAAGUUCCUGGAAAat-3′ (SEQ ID NO: 110)3′-CUAUAGUAGUGGUUCAAGGACCUUUUA-5′ (SEQ ID NO: 308) AAT-1167 Target:5′-GATATCATCACCAAGTTCCTGGAAAAT-3′ (SEQ ID NO: 506)5′-AUCAUCACCAAGUUCCUGGAAAAtg-3′ (SEQ ID NO: 111)3′-UAUAGUAGUGGUUCAAGGACCUUUUAC-5′ (SEQ ID NO: 309) AAT-1168 Target:5′-ATATCATCACCAAGTTCCTGGAAAATG-3′ (SEQ ID NO: 507)5′-UCAUCACCAAGUUCCUGGAAAAUga-3′ (SEQ ID NO: 112)3′-AUAGUAGUGGUUCAAGGACCUUUUACU-5′ (SEQ ID NO: 310) AAT-1169 Target:5′-TATCATCACCAAGTTCCTGGAAAATGA-3′ (SEQ ID NO: 508)5′-CAUCACCAAGUUCCUGGAAAAUGaa-3′ (SEQ ID NO: 113)3′-UAGUAGUGGUUCAAGGACCUUUUACUU-5′ (SEQ ID NO: 311) AAT-1170 Target:5′-ATCATCACCAAGTTCCTGGAAAATGAA-3′ (SEQ ID NO: 509)5′-AUCACCAAGUUCCUGGAAAAUGAag-3′ (SEQ ID NO: 114)3′-AGUAGUGGUUCAAGGACCUUUUACUUC-5′ (SEQ ID NO: 312) AAT-1171 Target:5′-TCATCACCAAGTTCCTGGAAAATGAAG-3′ (SEQ ID NO: 510)5′-UCACCAAGUUCCUGGAAAAUGAAga-3′ (SEQ ID NO: 115)3′-GUAGUGGUUCAAGGACCUUUUACUUCU-5′ (SEQ ID NO: 313) AAT-1172 Target:5′-CATCACCAAGTTCCTGGAAAATGAAGA-3′ (SEQ ID NO: 511)5′-CACCAAGUUCCUGGAAAAUGAAGac-3′ (SEQ ID NO: 116)3′-UAGUGGUUCAAGGACCUUUUACUUCUG-5′ (SEQ ID NO: 314) AAT-1173 Target:5′-ATCACCAAGTTCCTGGAAAATGAAGAC-3′ (SEQ ID NO: 512)5′-ACCAAGUUCCUGGAAAAUGAAGAca-3′ (SEQ ID NO: 117)3′-AGUGGUUCAAGGACCUUUUACUUCUGU-5′ (SEQ ID NO: 315) AAT-1174 Target:5′-TCACCAAGTTCCTGGAAAATGAAGACA-3′ (SEQ ID NO: 513)5′-CCAAGUUCCUGGAAAAUGAAGACag-3′ (SEQ ID NO: 118)3′-GUGGUUCAAGGACCUUUUACUUCUGUC-5′ (SEQ ID NO: 316) AAT-1175 Target:5′-CACCAAGTTCCTGGAAAATGAAGACAG-3′ (SEQ ID NO: 514)5′-AGGUCUUCAGCAAUGGGGCUGACct-3′ (SEQ ID NO: 119)3′-AUUCCAGAAGUCGUUACCCCGACUGGA-5′ (SEQ ID NO: 317) AAT-1286 Target:5′-TAAGGTCTTCAGCAATGGGGCTGACCT-3′ (SEQ ID NO: 515)5′-CAAUGGGGCUGACCUCUCCGGGGtc-3′ (SEQ ID NO: 120)3′-UCGUUACCCCGACUGGAGAGGCCCCAG-5′ (SEQ ID NO: 318) AAT-1296 Target:5′-AGCAATGGGGCTGACCTCTCCGGGGTC-3′ (SEQ ID NO: 516)5′-AAUGGGGCUGACCUCUCCGGGGUca-3′ (SEQ ID NO: 121)3′-CGUUACCCCGACUGGAGAGGCCCCAGU-5′ (SEQ ID NO: 319) AAT-1297 Target:5′-GCAATGGGGCTGACCTCTCCGGGGTCA-3′ (SEQ ID NO: 517)5′-AUGGGGCUGACCUCUCCGGGGUCac-3′ (SEQ ID NO: 122)3′-GUUACCCCGACUGGAGAGGCCCCAGUG-5′ (SEQ ID NO: 320) AAT-1298 Target:5′-CAATGGGGCTGACCTCTCCGGGGTCAC-3′ (SEQ ID NO: 518)5′-GAGGAGGCACCCCUGAAGCUCUCca-3′ (SEQ ID NO: 123)3′-GUCUCCUCCGUGGGGACUUCGAGAGGU-5′ (SEQ ID NO: 321) AAT-1324 Target:5′-CAGAGGAGGCACCCCTGAAGCTCTCCA-3′ (SEQ ID NO: 519)5′-GGAGGCACCCCUGAAGCUCUCCAag-3′ (SEQ ID NO: 124)3′-CUCCUCCGUGGGGACUUCGAGAGGUUC-5′ (SEQ ID NO: 322) AAT-1326 Target:5′-GAGGAGGCACCCCTGAAGCTCTCCAAG-3′ (SEQ ID NO: 520)5′-CUGAAGCUCUCCAAGGCCGUGCAta-3′ (SEQ ID NO: 125)3′-GGGACUUCGAGAGGUUCCGGCACGUAU-5′ (SEQ ID NO: 323) AAT-1336 Target:5′-CCCTGAAGCTCTCCAAGGCCGTGCATA-3′ (SEQ ID NO: 521)5′-CGUGCAUAAGGCUGUGCUGACCAtc-3′ (SEQ ID NO: 126)3′-CGGCACGUAUUCCGACACGACUGGUAG-5′ (SEQ ID NO: 324) AAT-1353 Target:5′-GCCGTGCATAAGGCTGTGCTGACCATC-3′ (SEQ ID NO: 522)5′-GUGCAUAAGGCUGUGCUGACCAUcg-3′ (SEQ ID NO: 127)3′-GGCACGUAUUCCGACACGACUGGUAGC-5′ (SEQ ID NO: 325) AAT-1354 Target:5′-CCGTGCATAAGGCTGTGCTGACCATCG-3′ (SEQ ID NO: 523)5′-UGCAUAAGGCUGUGCUGACCAUCga-3′ (SEQ ID NO: 128)3′-GCACGUAUUCCGACACGACUGGUAGCU-5′ (SEQ ID NO: 326) AAT-1355 Target:5′-CGTGCATAAGGCTGTGCTGACCATCGA-3′ (SEQ ID NO: 524)5′-GCAUAAGGCUGUGCUGACCAUCGac-3′ (SEQ ID NO: 129)3′-CACGUAUUCCGACACGACUGGUAGCUG-5′ (SEQ ID NO: 327) AAT-1356 Target:5′-GTGCATAAGGCTGTGCTGACCATCGAC-3′ (SEQ ID NO: 525)5′-CAUAAGGCUGUGCUGACCAUCGAcg-3′ (SEQ ID NO: 130)3′-ACGUAUUCCGACACGACUGGUAGCUGC-5′ (SEQ ID NO: 328) AAT-1357 Target:5′-TGCATAAGGCTGTGCTGACCATCGACG-3′ (SEQ ID NO: 526)5′-AUAAGGCUGUGCUGACCAUCGACga-3′ (SEQ ID NO: 131)3′-CGUAUUCCGACACGACUGGUAGCUGCU-5′ (SEQ ID NO: 329) AAT-1358 Target:5′-GCATAAGGCTGTGCTGACCATCGACGA-3′ (SEQ ID NO: 527)5′-UAAGGCUGUGCUGACCAUCGACGag-3′ (SEQ ID NO: 132)3′-GUAUUCCGACACGACUGGUAGCUGCUC-5′ (SEQ ID NO: 330) AAT-1359 Target:5′-CATAAGGCTGTGCTGACCATCGACGAG-3′ (SEQ ID NO: 528)5′-AAGGCUGUGCUGACCAUCGACGAga-3′ (SEQ ID NO: 133)3′-UAUUCCGACACGACUGGUAGCUGCUCU-5′ (SEQ ID NO: 331) AAT-1360 Target:5′-ATAAGGCTGTGCTGACCATCGACGAGA-3′ (SEQ ID NO: 529)5′-AGGCUGUGCUGACCAUCGACGAGaa-3′ (SEQ ID NO: 134)3′-AUUCCGACACGACUGGUAGCUGCUCUU-5′ (SEQ ID NO: 332) AAT-1361 Target:5′-TAAGGCTGTGCTGACCATCGACGAGAA-3′ (SEQ ID NO: 530)5′-ACUGAAGCUGCUGGGGCCAUGUUtt-3′ (SEQ ID NO: 135)3′-CCUGACUUCGACGACCCCGGUACAAAA-5′ (SEQ ID NO: 333) AAT-1390 Target:5′-GGACTGAAGCTGCTGGGGCCATGTTTT-3′ (SEQ ID NO: 531)5′-CUGAAGCUGCUGGGGCCAUGUUUtt-3′ (SEQ ID NO: 136)3′-CUGACUUCGACGACCCCGGUACAAAAA-5′ (SEQ ID NO: 334) AAT-1391 Target:5′-GACTGAAGCTGCTGGGGCCATGTTTTT-3′ (SEQ ID NO: 532)5′-UGAAGCUGCUGGGGCCAUGUUUUta-3′ (SEQ ID NO: 137)3′-UGACUUCGACGACCCCGGUACAAAAAU-5′ (SEQ ID NO: 335) AAT-1392 Target:5′-ACTGAAGCTGCTGGGGCCATGTTTTTA-3′ (SEQ ID NO: 533)5′-GAAGCUGCUGGGGCCAUGUUUUUag-3′ (SEQ ID NO: 138)3′-GACUUCGACGACCCCGGUACAAAAAUC-5′ (SEQ ID NO: 336) AAT-1393 Target:5′-CTGAAGCTGCTGGGGCCATGTTTTTAG-3′ (SEQ ID NO: 534)5′-AAGCUGCUGGGGCCAUGUUUUUAga-3′ (SEQ ID NO: 139)3′-ACUUCGACGACCCCGGUACAAAAAUCU-5′ (SEQ ID NO: 337) AAT-1394 Target:5′-TGAAGCTGCTGGGGCCATGTTTTTAGA-3′ (SEQ ID NO: 535)5′-AGCUGCUGGGGCCAUGUUUUUAGag-3′ (SEQ ID NO: 140)3′-CUUCGACGACCCCGGUACAAAAAUCUC-5′ (SEQ ID NO: 338) AAT-1395 Target:5′-GAAGCTGCTGGGGCCATGTTTTTAGAG-3′ (SEQ ID NO: 536)5′-GCCAUGUUUUUAGAGGCCAUACCca-3′ (SEQ ID NO: 141)3′-CCCGGUACAAAAAUCUCCGGUAUGGGU-5′ (SEQ ID NO: 339) AAT-1405 Target:5′-GGGCCATGTTTTTAGAGGCCATACCCA-3′ (SEQ ID NO: 537)5′-CCAUGUUUUUAGAGGCCAUACCCat-3′ (SEQ ID NO: 142)3′-CCGGUACAAAAAUCUCCGGUAUGGGUA-5′ (SEQ ID NO: 340) AAT-1406 Target:5′-GGCCATGTTTTTAGAGGCCATACCCAT-3′ (SEQ ID NO: 538)5′-CAUGUUUUUAGAGGCCAUACCCAtg-3′ (SEQ ID NO: 143)3′-CGGUACAAAAAUCUCCGGUAUGGGUAC-5′ (SEQ ID NO: 341) AAT-1407 Target:5′-GCCATGTTTTTAGAGGCCATACCCATG-3′ (SEQ ID NO: 539)5′-AUGUUUUUAGAGGCCAUACCCAUgt-3′ (SEQ ID NO: 144)3′-GGUACAAAAAUCUCCGGUAUGGGUACA-5′ (SEQ ID NO: 342) AAT-1408 Target:5′-CCATGTTTTTAGAGGCCATACCCATGT-3′ (SEQ ID NO: 540)5′-UGUUUUUAGAGGCCAUACCCAUGtc-3′ (SEQ ID NO: 145)3′-GUACAAAAAUCUCCGGUAUGGGUACAG-5′ (SEQ ID NO: 343) AAT-1409 Target:5′-CATGTTTTTAGAGGCCATACCCATGTC-3′ (SEQ ID NO: 541)5′-GUUUUUAGAGGCCAUACCCAUGUct-3′ (SEQ ID NO: 146)3′-UACAAAAAUCUCCGGUAUGGGUACAGA-5′ (SEQ ID NO: 344) AAT-1410 Target:5′-ATGTTTTTAGAGGCCATACCCATGTCT-3′ (SEQ ID NO: 542)5′-UUUUUAGAGGCCAUACCCAUGUCta-3′ (SEQ ID NO: 147)3′-ACAAAAAUCUCCGGUAUGGGUACAGAU-5′ (SEQ ID NO: 345) AAT-1411 Target:5′-TGTTTTTAGAGGCCATACCCATGTCTA-3′ (SEQ ID NO: 543)5′-UUUUAGAGGCCAUACCCAUGUCUat-3′ (SEQ ID NO: 148)3′-CAAAAAUCUCCGGUAUGGGUACAGAUA-5′ (SEQ ID NO: 346) AAT-1412 Target:5′-GTTTTTAGAGGCCATACCCATGTCTAT-3′ (SEQ ID NO: 544)5′-UUUAGAGGCCAUACCCAUGUCUAtc-3′ (SEQ ID NO: 149)3′-AAAAAUCUCCGGUAUGGGUACAGAUAG-5′ (SEQ ID NO: 347) AAT-1413 Target:5′-TTTTTAGAGGCCATACCCATGTCTATC-3′ (SEQ ID NO: 545)5′-UUAGAGGCCAUACCCAUGUCUAUcc-3′ (SEQ ID NO: 150)3′-AAAAUCUCCGGUAUGGGUACAGAUAGG-5′ (SEQ ID NO: 348) AAT-1414 Target:5′-TTTTAGAGGCCATACCCATGTCTATCC-3′ (SEQ ID NO: 546)5′-UAGAGGCCAUACCCAUGUCUAUCCC-3′ (SEQ ID NO: 151)3′-AAAUCUCCGGUAUGGGUACAGAUAGGG-5′ (SEQ ID NO: 349) AAT-1415 Target:5′-TTTAGAGGCCATACCCATGTCTATCCC-3′ (SEQ ID NO: 547)5′-AGAGGCCAUACCCAUGUCUAUCCCC-3′ (SEQ ID NO: 152)3′-AAUCUCCGGUAUGGGUACAGAUAGGGG-5′ (SEQ ID NO: 350) AAT-1416 Target:5′-TTAGAGGCCATACCCATGTCTATCCCC-3′ (SEQ ID NO: 548)5′-GUUCAACAAACCCUUUGUCUUCUta-3′ (SEQ ID NO: 153)3′-UUCAAGUUGUUUGGGAAACAGAAGAAU-5′ (SEQ ID NO: 351) AAT-1452 Target:5′-AAGTTCAACAAACCCTTTGTCTTCTTA-3′ (SEQ ID NO: 549)5′-UUCAACAAACCCUUUGUCUUCUUaa-3′ (SEQ ID NO: 154)3′-UCAAGUUGUUUGGGAAACAGAAGAAUU-5′ (SEQ ID NO: 352) AAT-1453 Target:5′-AGTTCAACAAACCCTTTGTCTTCTTAA-3′ (SEQ ID NO: 550)5′-UCAACAAACCCUUUGUCUUCUUAat-3′ (SEQ ID NO: 155)3′-CAAGUUGUUUGGGAAACAGAAGAAUUA-5′ (SEQ ID NO: 353) AAT-1454 Target:5′-GTTCAACAAACCCTTTGTCTTCTTAAT-3′ (SEQ ID NO: 551)5′-CAACAAACCCUUUGUCUUCUUAAtg-3′ (SEQ ID NO: 156)3′-AAGUUGUUUGGGAAACAGAAGAAUUAC-5′ (SEQ ID NO: 354) AAT-1455 Target:5′-TTCAACAAACCCTTTGTCTTCTTAATG-3′ (SEQ ID NO: 552)5′-AACAAACCCUUUGUCUUCUUAAUga-3′ (SEQ ID NO: 157)3′-AGUUGUUUGGGAAACAGAAGAAUUACU-5′ (SEQ ID NO: 355) AAT-1456 Target:5′-TCAACAAACCCTTTGTCTTCTTAATGA-3′ (SEQ ID NO: 553)5′-ACAAACCCUUUGUCUUCUUAAUGat-3′ (SEQ ID NO: 158)3′-GUUGUUUGGGAAACAGAAGAAUUACUA-5′ (SEQ ID NO: 356) AAT-1457 Target:5′-CAACAAACCCTTTGTCTTCTTAATGAT-3′ (SEQ ID NO: 554)5′-CAAACCCUUUGUCUUCUUAAUGAtt-3′ (SEQ ID NO: 159)3′-UUGUUUGGGAAACAGAAGAAUUACUAA-5′ (SEQ ID NO: 357) AAT-1458 Target:5′-AACAAACCCTTTGTCTTCTTAATGATT-3′ (SEQ ID NO: 555)5′-AAACCCUUUGUCUUCUUAAUGAUtg-3′ (SEQ ID NO: 160)3′-UGUUUGGGAAACAGAAGAAUUACUAAC-5′ (SEQ ID NO: 358) AAT-1459 Target:5′-ACAAACCCTTTGTCTTCTTAATGATTG-3′ (SEQ ID NO: 556)5′-AACCCUUUGUCUUCUUAAUGAUUga-3′ (SEQ ID NO: 161)3′-GUUUGGGAAACAGAAGAAUUACUAACU-5′ (SEQ ID NO: 359) AAT-1460 Target:5′-CAAACCCTTTGTCTTCTTAATGATTGA-3′ (SEQ ID NO: 557)5′-AAUACCAAGUCUCCCCUCUUCAUgg-3′ (SEQ ID NO: 162)3′-UUUUAUGGUUCAGAGGGGAGAAGUACC-5′ (SEQ ID NO: 360) AAT-1489 Target:5′-AAAATACCAAGTCTCCCCTCTTCATGG-3′ (SEQ ID NO: 558)5′-AUACCAAGUCUCCCCUCUUCAUGgg-3′ (SEQ ID NO: 163)3′-UUUAUGGUUCAGAGGGGAGAAGUACCC-5′ (SEQ ID NO: 361) AAT-1490 Target:5′-AAATACCAAGTCTCCCCTCTTCATGGG-3′ (SEQ ID NO: 559)5′-UACCAAGUCUCCCCUCUUCAUGGga-3′ (SEQ ID NO: 164)3′-UUAUGGUUCAGAGGGGAGAAGUACCCU-5′ (SEQ ID NO: 362) AAT-1491 Target:5′-AATACCAAGTCTCCCCTCTTCATGGGA-3′ (SEQ ID NO: 560)5′-ACCAAGUCUCCCCUCUUCAUGGGaa-3′ (SEQ ID NO: 165)3′-UAUGGUUCAGAGGGGAGAAGUACCCUU-5′ (SEQ ID NO: 363) AAT-1492 Target:5′-ATACCAAGTCTCCCCTCTTCATGGGAA-3′ (SEQ ID NO: 561)5′-CCAAGUCUCCCCUCUUCAUGGGAaa-3′ (SEQ ID NO: 166)3′-AUGGUUCAGAGGGGAGAAGUACCCUUU-5′ (SEQ ID NO: 364) AAT-1493 Target:5′-TACCAAGTCTCCCCTCTTCATGGGAAA-3′ (SEQ ID NO: 562)5′-CAAGUCUCCCCUCUUCAUGGGAAaa-3′ (SEQ ID NO: 167)3′-UGGUUCAGAGGGGAGAAGUACCCUUUU-5′ (SEQ ID NO: 365) AAT-1494 Target:5′-ACCAAGTCTCCCCTCTTCATGGGAAAA-3′ (SEQ ID NO: 563)5′-AAGUCUCCCCUCUUCAUGGGAAAag-3′ (SEQ ID NO: 168)3′-GGUUCAGAGGGGAGAAGUACCCUUUUC-5′ (SEQ ID NO: 366) AAT-1495 Target:5′-CCAAGTCTCCCCTCTTCATGGGAAAAG-3′ (SEQ ID NO: 564)5′-AGUCUCCCCUCUUCAUGGGAAAAgt-3′ (SEQ ID NO: 169)3′-GUUCAGAGGGGAGAAGUACCCUUUUCA-5′ (SEQ ID NO: 367) AAT-1496 Target:5′-CAAGTCTCCCCTCTTCATGGGAAAAGT-3′ (SEQ ID NO: 565)5′-GUCUCCCCUCUUCAUGGGAAAAGtg-3′ (SEQ ID NO: 170)3′-UUCAGAGGGGAGAAGUACCCUUUUCAC-5′ (SEQ ID NO: 368) AAT-1497 Target:5′-AAGTCTCCCCTCTTCATGGGAAAAGTG-3′ (SEQ ID NO: 566)5′-CUCCCCUCUUCAUGGGAAAAGUGgt-3′ (SEQ ID NO: 171)3′-CAGAGGGGAGAAGUACCCUUUUCACCA-5′ (SEQ ID NO: 369) AAT-1499 Target:5′-GTCTCCCCTCTTCATGGGAAAAGTGGT-3′ (SEQ ID NO: 567)5′-CCCCUCUUCAUGGGAAAAGUGGUga-3′ (SEQ ID NO: 172)3′-GAGGGGAGAAGUACCCUUUUCACCACU-5′ (SEQ ID NO: 370) AAT-1501 Target:5′-CTCCCCTCTTCATGGGAAAAGTGGTGA-3′ (SEQ ID NO: 568)5′-CCCUCUUCAUGGGAAAAGUGGUGaa-3′ (SEQ ID NO: 173)3′-AGGGGAGAAGUACCCUUUUCACCACUU-5′ (SEQ ID NO: 371) AAT-1502 Target:5′-TCCCCTCTTCATGGGAAAAGTGGTGAA-3′ (SEQ ID NO: 569)5′-CCUCUUCAUGGGAAAAGUGGUGAat-3′ (SEQ ID NO: 174)3′-GGGGAGAAGUACCCUUUUCACCACUUA-5′ (SEQ ID NO: 372) AAT-1503 Target:5′-CCCCTCTTCATGGGAAAAGTGGTGAAT-3′ (SEQ ID NO: 570)5′-CUCUUCAUGGGAAAAGUGGUGAAtc-3′ (SEQ ID NO: 175)3′-GGGAGAAGUACCCUUUUCACCACUUAG-5′ (SEQ ID NO: 373) AAT-1504 Target:5′-CCCTCTTCATGGGAAAAGTGGTGAATC-3′ (SEQ ID NO: 571)5′-UCUUCAUGGGAAAAGUGGUGAAUcC-3′ (SEQ ID NO: 176)3′-GGAGAAGUACCCUUUUCACCACUUAGG-5′ (SEQ ID NO: 374) AAT-1505 Target:5′-CCTCTTCATGGGAAAAGTGGTGAATCC-3′ (SEQ ID NO: 572)5′-CUUCAUGGGAAAAGUGGUGAAUCCC-3′ (SEQ ID NO: 177)3′-GAGAAGUACCCUUUUCACCACUUAGGG-5′ (SEQ ID NO: 375) AAT-1506 Target:5′-CTCTTCATGGGAAAAGTGGTGAATCCC-3′ (SEQ ID NO: 573)5′-UUCAUGGGAAAAGUGGUGAAUCCca-3′ (SEQ ID NO: 178)3′-AGAAGUACCCUUUUCACCACUUAGGGU-5′ (SEQ ID NO: 376) AAT-1507 Target:5′-TCTTCATGGGAAAAGTGGTGAATCCCA-3′ (SEQ ID NO: 574)5′-UCAUGGGAAAAGUGGUGAAUCCCac-3′ (SEQ ID NO: 179)3′-GAAGUACCCUUUUCACCACUUAGGGUG-5′ (SEQ ID NO: 377) AAT-1508 Target:5′-CTTCATGGGAAAAGTGGTGAATCCCAC-3′ (SEQ ID NO: 575)5′-CAUGGGAAAAGUGGUGAAUCCCACC-3′ (SEQ ID NO: 180)3′-AAGUACCCUUUUCACCACUUAGGGUGG-5′ (SEQ ID NO: 378) AAT-1509 Target:5′-TTCATGGGAAAAGTGGTGAATCCCACC-3′ (SEQ ID NO: 576)5′-AUGGGAAAAGUGGUGAAUCCCACcC-3′ (SEQ ID NO: 181)3′-AGUACCCUUUUCACCACUUAGGGUGGG-5′ (SEQ ID NO: 379) AAT-1510 Target:5′-TCATGGGAAAAGTGGTGAATCCCACCC-3′ (SEQ ID NO: 577)5′-UGGGAAAAGUGGUGAAUCCCACCca-3′ (SEQ ID NO: 182)3′-GUACCCUUUUCACCACUUAGGGUGGGU-5′ (SEQ ID NO: 380) AAT-1511 Target:5′-CATGGGAAAAGTGGTGAATCCCACCCA-3′ (SEQ ID NO: 578)5′-GGGAAAAGUGGUGAAUCCCACCCaa-3′ (SEQ ID NO: 183)3′-UACCCUUUUCACCACUUAGGGUGGGUU-5′ (SEQ ID NO: 381) AAT-1512 Target:5′-ATGGGAAAAGTGGTGAATCCCACCCAA-3′ (SEQ ID NO: 579)5′-GGAAAAGUGGUGAAUCCCACCCAaa-3′ (SEQ ID NO: 184)3′-ACCCUUUUCACCACUUAGGGUGGGUUU-5′ (SEQ ID NO: 382) AAT-1513 Target:5′-TGGGAAAAGTGGTGAATCCCACCCAAA-3′ (SEQ ID NO: 580)5′-GAAAAGUGGUGAAUCCCACCCAAaa-3′ (SEQ ID NO: 185)3′-CCCUUUUCACCACUUAGGGUGGGUUUU-5′ (SEQ ID NO: 383) AAT-1514 Target:5′-GGGAAAAGTGGTGAATCCCACCCAAAA-3′ (SEQ ID NO: 581)5′-AAAAGUGGUGAAUCCCACCCAAAaa-3′ (SEQ ID NO: 186)3′-CCUUUUCACCACUUAGGGUGGGUUUUU-5′ (SEQ ID NO: 384) AAT-1515 Target:5′-GGAAAAGTGGTGAATCCCACCCAAAAA-3′ (SEQ ID NO: 582)5′-AAAGUGGUGAAUCCCACCCAAAAat-3′ (SEQ ID NO: 187)3′-CUUUUCACCACUUAGGGUGGGUUUUUA-5′ (SEQ ID NO: 385) AAT-1516 Target:5′-GAAAAGTGGTGAATCCCACCCAAAAAT-3′ (SEQ ID NO: 583)5′-AAGUGGUGAAUCCCACCCAAAAAta-3′ (SEQ ID NO: 188)3′-UUUUCACCACUUAGGGUGGGUUUUUAU-5′ (SEQ ID NO: 386) AAT-1517 Target:5′-AAAAGTGGTGAATCCCACCCAAAAATA-3′ (SEQ ID NO: 584)5′-CGAUAGUUCAAAAUGGUGAAAUUag-3′ (SEQ ID NO: 189)3′-AAGCUAUCAAGUUUUACCACUUUAAUC-5′ (SEQ ID NO: 387) AAT-2872 Target:5′-TTCGATAGTTCAAAATGGTGAAATTAG-3′ (SEQ ID NO: 585)5′-CAAAAUGGUGAAAUUAGCAAUUCta-3′ (SEQ ID NO: 190)3′-AAGUUUUACCACUUUAAUCGUUAAGAU-5′ (SEQ ID NO: 388) AAT-2880 Target:5′-TTCAAAATGGTGAAATTAGCAATTCTA-3′ (SEQ ID NO: 586)5′-UUGGUAUGAUGUUCAAGUUAGAUaa-3′ (SEQ ID NO: 191)3′-UCAACCAUACUACAAGUUCAAUCUAUU-5′ (SEQ ID NO: 389) AAT-3167 Target:5′-AGTTGGTATGATGTTCAAGTTAGATAA-3′ (SEQ ID NO: 587)5′-GGUAUGAUGUUCAAGUUAGAUAAca-3′ (SEQ ID NO: 192)3′-AACCAUACUACAAGUUCAAUCUAUUGU-5′ (SEQ ID NO: 390) AAT-3169 Target:5′-TTGGTATGATGTTCAAGTTAGATAACA-3′ (SEQ ID NO: 588)5′-GUAUGAUGUUCAAGUUAGAUAACaa-3′ (SEQ ID NO: 193)3′-ACCAUACUACAAGUUCAAUCUAUUGUU-5′ (SEQ ID NO: 391) AAT-3170 Target:5′-TGGTATGATGTTCAAGTTAGATAACAA-3′ (SEQ ID NO: 589)5′-AUGAUGUUCAAGUUAGAUAACAAaa-3′ (SEQ ID NO: 194)3′-CAUACUACAAGUUCAAUCUAUUGUUUU-5′ (SEQ ID NO: 392) AAT-3172 Target:5′-GTATGATGTTCAAGTTAGATAACAAAA-3′ (SEQ ID NO: 590)5′-AUGUUCAAGUUAGAUAACAAAAUgt-3′ (SEQ ID NO: 195)3′-ACUACAAGUUCAAUCUAUUGUUUUACA-5′ (SEQ ID NO: 393) AAT-3175 Target:5′-TGATGTTCAAGTTAGATAACAAAATGT-3′ (SEQ ID NO: 591)5′-CAAGUUAGAUAACAAAAUGUUUAta-3′ (SEQ ID NO: 196)3′-AAGUUCAAUCUAUUGUUUUACAAAUAU-5′ (SEQ ID NO: 394) AAT-3180 Target:5′-TTCAAGTTAGATAACAAAATGTTTATA-3′ (SEQ ID NO: 592)5′-AAGUUAGAUAACAAAAUGUUUAUac-3′ (SEQ ID NO: 197)3′-AGUUCAAUCUAUUGUUUUACAAAUAUG-5′ (SEQ ID NO: 395) AAT-3181 Target:5′-TCAAGTTAGATAACAAAATGTTTATAC-3′ (SEQ ID NO: 593)5′-AGUUAGAUAACAAAAUGUUUAUAcc-3′ (SEQ ID NO: 198)3′-GUUCAAUCUAUUGUUUUACAAAUAUGG-5′ (SEQ ID NO: 396) AAT-3182 Target:5′-CAAGTTAGATAACAAAATGTTTATACC-3′ (SEQ ID NO: 594)

TABLE 3 Selected Human Anti-α-1 antitrypsin DsiRNAs, Unmodified Duplexes(Asymmetries) 5′-CAUCCCACCAUGAUCAGGAUCACCC-3′ (SEQ ID NO: 595)3′-AUGUAGGGUGGUACUAGUCCUAGUGGG-5′ (SEQ ID NO: 199) AAT-395 Target:5′-TACATCCCACCATGATCAGGATCACCC-3′ (SEQ ID NO: 397)5′-CAGCUGGCACACCAGUCCAACAGCA-3′ (SEQ ID NO: 596)3′-CGGUCGACCGUGUGGUCAGGUUGUCGU-5′ (SEQ ID NO: 200) AAT-475 Target:5′-GCCAGCTGGCACACCAGTCCAACAGCA-3′ (SEQ ID NO: 398)5′-GCUGGCACACCAGUCCAACAGCACC-3′ (SEQ ID NO: 597)3′-GUCGACCGUGUGGUCAGGUUGUCGUGG-5′ (SEQ ID NO: 201) AAT-477 Target:5′-CAGCTGGCACACCAGTCCAACAGCACC-3′ (SEQ ID NO: 399)5′-GGCACACCAGUCCAACAGCACCAAU-3′ (SEQ ID NO: 598)3′-GACCGUGUGGUCAGGUUGUCGUGGUUA-5′ (SEQ ID NO: 202) AAT-480 Target:5′-CTGGCACACCAGTCCAACAGCACCAAT-3′ (SEQ ID NO: 400)5′-GCACACCAGUCCAACAGCACCAAUA-3′ (SEQ ID NO: 599)3′-ACCGUGUGGUCAGGUUGUCGUGGUUAU-5′ (SEQ ID NO: 203) AAT-481 Target:5′-TGGCACACCAGTCCAACAGCACCAATA-3′ (SEQ ID NO: 401)5′-CACACCAGUCCAACAGCACCAAUAU-3′ (SEQ ID NO: 600)3′-CCGUGUGGUCAGGUUGUCGUGGUUAUA-5′ (SEQ ID NO: 204) AAT-482 Target:5′-GGCACACCAGTCCAACAGCACCAATAT-3′ (SEQ ID NO: 402)5′-ACACCAGUCCAACAGCACCAAUAUC-3′ (SEQ ID NO: 601)3′-CGUGUGGUCAGGUUGUCGUGGUUAUAG-5′ (SEQ ID NO: 205) AAT-483 Target:5′-GCACACCAGTCCAACAGCACCAATATC-3′ (SEQ ID NO: 403)5′-CACCAGUCCAACAGCACCAAUAUCU-3′ (SEQ ID NO: 602)3′-GUGUGGUCAGGUUGUCGUGGUUAUAGA-5′ (SEQ ID NO: 206) AAT-484 Target:5′-CACACCAGTCCAACAGCACCAATATCT-3′ (SEQ ID NO: 404)5′-CCAAUAUCUUCUUCUCCCCAGUGAG-3′ (SEQ ID NO: 603)3′-GUGGUUAUAGAAGAAGAGGGGUCACUC-5′ (SEQ ID NO: 207) AAT-500 Target:5′-CACCAATATCTTCTTCTCCCCAGTGAG-3′ (SEQ ID NO: 405)5′-CAAUAUCUUCUUCUCCCCAGUGAGC-3′ (SEQ ID NO: 604)3′-UGGUUAUAGAAGAAGAGGGGUCACUCG-5′ (SEQ ID NO: 208) AAT-501 Target:5′-ACCAATATCTTCTTCTCCCCAGTGAGC-3′ (SEQ ID NO: 406)5′-AAUAUCUUCUUCUCCCCAGUGAGCA-3′ (SEQ ID NO: 605)3′-GGUUAUAGAAGAAGAGGGGUCACUCGU-5′ (SEQ ID NO: 209) AAT-502 Target:5′-CCAATATCTTCTTCTCCCCAGTGAGCA-3′ (SEQ ID NO: 407)5′-AUAUCUUCUUCUCCCCAGUGAGCAU-3′ (SEQ ID NO: 606)3′-GUUAUAGAAGAAGAGGGGUCACUCGUA-5′ (SEQ ID NO: 210) AAT-503 Target:5′-CAATATCTTCTTCTCCCCAGTGAGCAT-3′ (SEQ ID NO: 408)5′-UAUCUUCUUCUCCCCAGUGAGCAUC-3′ (SEQ ID NO: 607)3′-UUAUAGAAGAAGAGGGGUCACUCGUAG-5′ (SEQ ID NO: 211) AAT-504 Target:5′-AATATCTTCTTCTCCCCAGTGAGCATC-3′ (SEQ ID NO: 409)5′-AUCUUCUUCUCCCCAGUGAGCAUCG-3′ (SEQ ID NO: 608)3′-UAUAGAAGAAGAGGGGUCACUCGUAGC-5′ (SEQ ID NO: 212) AAT-505 Target:5′-ATATCTTCTTCTCCCCAGTGAGCATCG-3′ (SEQ ID NO: 410)5′-UCUUCUUCUCCCCAGUGAGCAUCGC-3′ (SEQ ID NO: 609)3′-AUAGAAGAAGAGGGGUCACUCGUAGCG-5′ (SEQ ID NO: 213) AAT-506 Target:5′-TATCTTCTTCTCCCCAGTGAGCATCGC-3′ (SEQ ID NO: 411)5′-CUUCUUCUCCCCAGUGAGCAUCGCU-3′ (SEQ ID NO: 610)3′-UAGAAGAAGAGGGGUCACUCGUAGCGA-5′ (SEQ ID NO: 214) AAT-507 Target:5′-ATCTTCTTCTCCCCAGTGAGCATCGCT-3′ (SEQ ID NO: 412)5′-UUCUUCUCCCCAGUGAGCAUCGCUA-3′ (SEQ ID NO: 611)3′-AGAAGAAGAGGGGUCACUCGUAGCGAU-5′ (SEQ ID NO: 215) AAT-508 Target:5′-TCTTCTTCTCCCCAGTGAGCATCGCTA-3′ (SEQ ID NO: 413)5′-UCUUCUCCCCAGUGAGCAUCGCUAC-3′ (SEQ ID NO: 612)3′-GAAGAAGAGGGGUCACUCGUAGCGAUG-5′ (SEQ ID NO: 216) AAT-509 Target:5′-CTTCTTCTCCCCAGTGAGCATCGCTAC-3′ (SEQ ID NO: 414)5′-CUUCUCCCCAGUGAGCAUCGCUACA-3′ (SEQ ID NO: 613)3′-AAGAAGAGGGGUCACUCGUAGCGAUGU-5′ (SEQ ID NO: 217) AAT-510 Target:5′-TTCTTCTCCCCAGTGAGCATCGCTACA-3′ (SEQ ID NO: 415)5′-UCUCCCCAGUGAGCAUCGCUACAGC-3′ (SEQ ID NO: 614)3′-GAAGAGGGGUCACUCGUAGCGAUGUCG-5′ (SEQ ID NO: 218) AAT-512 Target:5′-CTTCTCCCCAGTGAGCATCGCTACAGC-3′ (SEQ ID NO: 416)5′-CUCCCCAGUGAGCAUCGCUACAGCC-3′ (SEQ ID NO: 615)3′-AAGAGGGGUCACUCGUAGCGAUGUCGG-5′ (SEQ ID NO: 219) AAT-513 Target:5′-TTCTCCCCAGTGAGCATCGCTACAGCC-3′ (SEQ ID NO: 417)5′-CCCCAGUGAGCAUCGCUACAGCCUU-3′ (SEQ ID NO: 616)3′-GAGGGGUCACUCGUAGCGAUGUCGGAA-5′ (SEQ ID NO: 220) AAT-515 Target:5′-CTCCCCAGTGAGCATCGCTACAGCCTT-3′ (SEQ ID NO: 418)5′-ACAGCCUUUGCAAUGCUCUCCCUGG-3′ (SEQ ID NO: 617)3′-GAUGUCGGAAACGUUACGAGAGGGACC-5′ (SEQ ID NO: 221) AAT-532 Target:5′-CTACAGCCTTTGCAATGCTCTCCCTGG-3′ (SEQ ID NO: 419)5′-UGCAAUGCUCUCCCUGGGGACCAAG-3′ (SEQ ID NO: 618)3′-AAACGUUACGAGAGGGACCCCUGGUUC-5′ (SEQ ID NO: 222) AAT-540 Target:5′-TTTGCAATGCTCTCCCTGGGGACCAAG-3′ (SEQ ID NO: 420)5′-AAAUCCUGGAGGGCCUGAAUUUCAA-3′ (SEQ ID NO: 619)3′-ACUUUAGGACCUCCCGGACUUAAAGUU-5′ (SEQ ID NO: 223) AAT-581 Target:5′-TGAAATCCTGGAGGGCCTGAATTTCAA-3′ (SEQ ID NO: 421)5′-AAUCCUGGAGGGCCUGAAUUUCAAC-3′ (SEQ ID NO: 620)3′-CUUUAGGACCUCCCGGACUUAAAGUUG-5′ (SEQ ID NO: 224) AAT-582 Target:5′-GAAATCCTGGAGGGCCTGAATTTCAAC-3′ (SEQ ID NO: 422)5′-AUCCUGGAGGGCCUGAAUUUCAACC-3′ (SEQ ID NO: 621)3′-UUUAGGACCUCCCGGACUUAAAGUUGG-5′ (SEQ ID NO: 225) AAT-583 Target:5′-AAATCCTGGAGGGCCTGAATTTCAACC-3′ (SEQ ID NO: 423)5′-CCUGGAGGGCCUGAAUUUCAACCUC-3′ (SEQ ID NO: 622)3′-UAGGACCUCCCGGACUUAAAGUUGGAG-5′ (SEQ ID NO: 226) AAT-585 Target:5′-ATCCTGGAGGGCCTGAATTTCAACCTC-3′ (SEQ ID NO: 424)5′-CUGGAGGGCCUGAAUUUCAACCUCA-3′ (SEQ ID NO: 623)3′-AGGACCUCCCGGACUUAAAGUUGGAGU-5′ (SEQ ID NO: 227) AAT-586 Target:5′-TCCTGGAGGGCCTGAATTTCAACCTCA-3′ (SEQ ID NO: 425)5′-UGGAGGGCCUGAAUUUCAACCUCAC-3′ (SEQ ID NO: 624)3′-GGACCUCCCGGACUUAAAGUUGGAGUG-5′ (SEQ ID NO: 228) AAT-587 Target:5′-CCTGGAGGGCCTGAATTTCAACCTCAC-3′ (SEQ ID NO: 426)5′-CAUGAAGGCUUCCAGGAACUCCUCC-3′ (SEQ ID NO: 625)3′-AGGUACUUCCGAAGGUCCUUGAGGAGG-5′ (SEQ ID NO: 229) AAT-634 Target:5′-TCCATGAAGGCTTCCAGGAACTCCTCC-3′ (SEQ ID NO: 427)5′-GAAGGCUUCCAGGAACUCCUCCGUA-3′ (SEQ ID NO: 626)3′-UACUUCCGAAGGUCCUUGAGGAGGCAU-5′ (SEQ ID NO: 230) AAT-637 Target:5′-ATGAAGGCTTCCAGGAACTCCTCCGTA-3′ (SEQ ID NO: 428)5′-AAGGCUUCCAGGAACUCCUCCGUAC-3′ (SEQ ID NO: 627)3′-ACUUCCGAAGGUCCUUGAGGAGGCAUG-5′ (SEQ ID NO: 231) AAT-638 Target:5′-TGAAGGCTTCCAGGAACTCCTCCGTAC-3′ (SEQ ID NO: 429)5′-AGCCAGACAGCCAGCUCCAGCUGAC-3′ (SEQ ID NO: 628)3′-GGUCGGUCUGUCGGUCGAGGUCGACUG-5′ (SEQ ID NO: 232) AAT-671 Target:5′-CCAGCCAGACAGCCAGCTCCAGCTGAC-3′ (SEQ ID NO: 430)5′-CCAGACAGCCAGCUCCAGCUGACCA-3′ (SEQ ID NO: 629)3′-UCGGUCUGUCGGUCGAGGUCGACUGGU-5′ (SEQ ID NO: 233) AAT-673 Target:5′-AGCCAGACAGCCAGCTCCAGCTGACCA-3′ (SEQ ID NO: 431)5′-AGACAGCCAGCUCCAGCUGACCACC-3′ (SEQ ID NO: 630)3′-GGUCUGUCGGUCGAGGUCGACUGGUGG-5′ (SEQ ID NO: 234) AAT-675 Target:5′-CCAGACAGCCAGCTCCAGCTGACCACC-3′ (SEQ ID NO: 432)5′-GACAGCCAGCUCCAGCUGACCACCG-3′ (SEQ ID NO: 631)3′-GUCUGUCGGUCGAGGUCGACUGGUGGC-5′ (SEQ ID NO: 235) AAT-676 Target:5′-CAGACAGCCAGCTCCAGCTGACCACCG-3′ (SEQ ID NO: 433)5′-UAGUGGAUAAGUUUUUGGAGGAUGU-3′ (SEQ ID NO: 632)3′-CGAUCACCUAUUCAAAAACCUCCUACA-5′ (SEQ ID NO: 236) AAT-734 Target:5′-GCTAGTGGATAAGTTTTTGGAGGATGT-3′ (SEQ ID NO: 434)5′-AGUGGAUAAGUUUUUGGAGGAUGUU-3′ (SEQ ID NO: 633)3′-GAUCACCUAUUCAAAAACCUCCUACAA-5′ (SEQ ID NO: 237) AAT-735 Target:5′-CTAGTGGATAAGTTTTTGGAGGATGTT-3′ (SEQ ID NO: 435)5′-GUGGAUAAGUUUUUGGAGGAUGUUA-3′ (SEQ ID NO: 634)3′-AUCACCUAUUCAAAAACCUCCUACAAU-5′ (SEQ ID NO: 238) AAT-736 Target:5′-TAGTGGATAAGTTTTTGGAGGATGTTA-3′ (SEQ ID NO: 436)5′-UGGAUAAGUUUUUGGAGGAUGUUAA-3′ (SEQ ID NO: 635)3′-UCACCUAUUCAAAAACCUCCUACAAUU-5′ (SEQ ID NO: 239) AAT-737 Target:5′-AGTGGATAAGTTTTTGGAGGATGTTAA-3′ (SEQ ID NO: 437)5′-GGAUAAGUUUUUGGAGGAUGUUAAA-3′ (SEQ ID NO: 636)3′-CACCUAUUCAAAAACCUCCUACAAUUU-5′ (SEQ ID NO: 240) AAT-738 Target:5′-GTGGATAAGTTTTTGGAGGATGTTAAA-3′ (SEQ ID NO: 438)5′-GAUAAGUUUUUGGAGGAUGUUAAAA-3′ (SEQ ID NO: 637)3′-ACCUAUUCAAAAACCUCCUACAAUUUU-5′ (SEQ ID NO: 241) AAT-739 Target:5′-TGGATAAGTTTTTGGAGGATGTTAAAA-3′ (SEQ ID NO: 439)5′-AUAAGUUUUUGGAGGAUGUUAAAAA-3′ (SEQ ID NO: 638)3′-CCUAUUCAAAAACCUCCUACAAUUUUU-5′ (SEQ ID NO: 242) AAT-740 Target:5′-GGATAAGTTTTTGGAGGATGTTAAAAA-3′ (SEQ ID NO: 440)5′-UGUACCACUCAGAAGCCUUCACUGU-3′ (SEQ ID NO: 639)3′-CAACAUGGUGAGUCUUCGGAAGUGACA-5′ (SEQ ID NO: 243) AAT-767 Target:5′-GTTGTACCACTCAGAAGCCTTCACTGT-3′ (SEQ ID NO: 441)5′-GUACCACUCAGAAGCCUUCACUGUC-3′ (SEQ ID NO: 640)3′-AACAUGGUGAGUCUUCGGAAGUGACAG-5′ (SEQ ID NO: 244) AAT-768 Target:5′-TTGTACCACTCAGAAGCCTTCACTGTC-3′ (SEQ ID NO: 442)5′-ACUCAAGGGAAAAUUGUGGAUUUGG-3′ (SEQ ID NO: 641)3′-CAUGAGUUCCCUUUUAACACCUAAACC-5′ (SEQ ID NO: 245) AAT-850 Target:5′-GTACTCAAGGGAAAATTGTGGATTTGG-3′ (SEQ ID NO: 443)5′-CUCAAGGGAAAAUUGUGGAUUUGGU-3′ (SEQ ID NO: 642)3′-AUGAGUUCCCUUUUAACACCUAAACCA-5′ (SEQ ID NO: 246) AAT-851 Target:5′-TACTCAAGGGAAAATTGTGGATTTGGT-3′ (SEQ ID NO: 444)5′-UCAAGGGAAAAUUGUGGAUUUGGUC-3′ (SEQ ID NO: 643)3′-UGAGUUCCCUUUUAACACCUAAACCAG-5′ (SEQ ID NO: 247) AAT-852 Target:5′-ACTCAAGGGAAAATTGTGGATTTGGTC-3′ (SEQ ID NO: 445)5′-CAAGGGAAAAUUGUGGAUUUGGUCA-3′ (SEQ ID NO: 644)3′-GAGUUCCCUUUUAACACCUAAACCAGU-5′ (SEQ ID NO: 248) AAT-853 Target:5′-CTCAAGGGAAAATTGTGGATTTGGTCA-3′ (SEQ ID NO: 446)5′-AAGGGAAAAUUGUGGAUUUGGUCAA-3′ (SEQ ID NO: 645)3′-AGUUCCCUUUUAACACCUAAACCAGUU-5′ (SEQ ID NO: 249) AAT-854 Target:5′-TCAAGGGAAAATTGTGGATTTGGTCAA-3′ (SEQ ID NO: 447)5′-AGGGAAAAUUGUGGAUUUGGUCAAG-3′ (SEQ ID NO: 646)3′-GUUCCCUUUUAACACCUAAACCAGUUC-5′ (SEQ ID NO: 250) AAT-855 Target:5′-CAAGGGAAAATTGTGGATTTGGTCAAG-3′ (SEQ ID NO: 448)5′-GGGAAAAUUGUGGAUUUGGUCAAGG-3′ (SEQ ID NO: 647)3′-UUCCCUUUUAACACCUAAACCAGUUCC-5′ (SEQ ID NO: 251) AAT-856 Target:5′-AAGGGAAAATTGTGGATTTGGTCAAGG-3′ (SEQ ID NO: 449)5′-GGAAAAUUGUGGAUUUGGUCAAGGA-3′ (SEQ ID NO: 648)3′-UCCCUUUUAACACCUAAACCAGUUCCU-5′ (SEQ ID NO: 252) AAT-857 Target:5′-AGGGAAAATTGTGGATTTGGTCAAGGA-3′ (SEQ ID NO: 450)5′-GAAAAUUGUGGAUUUGGUCAAGGAG-3′ (SEQ ID NO: 649)3′-CCCUUUUAACACCUAAACCAGUUCCUC-5′ (SEQ ID NO: 253) AAT-858 Target:5′-GGGAAAATTGTGGATTTGGTCAAGGAG-3′ (SEQ ID NO: 451)5′-AAAAUUGUGGAUUUGGUCAAGGAGC-3′ (SEQ ID NO: 650)3′-CCUUUUAACACCUAAACCAGUUCCUCG-5′ (SEQ ID NO: 254) AAT-859 Target:5′-GGAAAATTGTGGATTTGGTCAAGGAGC-3′ (SEQ ID NO: 452)5′-AAAUUGUGGAUUUGGUCAAGGAGCU-3′ (SEQ ID NO: 651)3′-CUUUUAACACCUAAACCAGUUCCUCGA-5′ (SEQ ID NO: 255) AAT-860 Target:5′-GAAAATTGTGGATTTGGTCAAGGAGCT-3′ (SEQ ID NO: 453)5′-AAUUGUGGAUUUGGUCAAGGAGCUU-3′ (SEQ ID NO: 652)3′-UUUUAACACCUAAACCAGUUCCUCGAA-5′ (SEQ ID NO: 256) AAT-861 Target:5′-AAAATTGTGGATTTGGTCAAGGAGCTT-3′ (SEQ ID NO: 454)5′-AUUGUGGAUUUGGUCAAGGAGCUUG-3′ (SEQ ID NO: 653)3′-UUUAACACCUAAACCAGUUCCUCGAAC-5′ (SEQ ID NO: 257) AAT-862 Target:5′-AAATTGTGGATTTGGTCAAGGAGCTTG-3′ (SEQ ID NO: 455)5′-UUGUGGAUUUGGUCAAGGAGCUUGA-3′ (SEQ ID NO: 654)3′-UUAACACCUAAACCAGUUCCUCGAACU-5′ (SEQ ID NO: 258) AAT-863 Target:5′-AATTGTGGATTTGGTCAAGGAGCTTGA-3′ (SEQ ID NO: 456)5′-UGUGGAUUUGGUCAAGGAGCUUGAC-3′ (SEQ ID NO: 655)3′-UAACACCUAAACCAGUUCCUCGAACUG-5′ (SEQ ID NO: 259) AAT-864 Target:5′-ATTGTGGATTTGGTCAAGGAGCTTGAC-3′ (SEQ ID NO: 457)5′-GUGGAUUUGGUCAAGGAGCUUGACA-3′ (SEQ ID NO: 656)3′-AACACCUAAACCAGUUCCUCGAACUGU-5′ (SEQ ID NO: 260) AAT-865 Target:5′-TTGTGGATTTGGTCAAGGAGCTTGACA-3′ (SEQ ID NO: 458)5′-UGGAUUUGGUCAAGGAGCUUGACAG-3′ (SEQ ID NO: 657)3′-ACACCUAAACCAGUUCCUCGAACUGUC-5′ (SEQ ID NO: 261) AAT-866 Target:5′-TGTGGATTTGGTCAAGGAGCTTGACAG-3′ (SEQ ID NO: 459)5′-GGAUUUGGUCAAGGAGCUUGACAGA-3′ (SEQ ID NO: 658)3′-CACCUAAACCAGUUCCUCGAACUGUCU-5′ (SEQ ID NO: 262) AAT-867 Target:5′-GTGGATTTGGTCAAGGAGCTTGACAGA-3′ (SEQ ID NO: 460)5′-GAUUUGGUCAAGGAGCUUGACAGAG-3′ (SEQ ID NO: 659)3′-ACCUAAACCAGUUCCUCGAACUGUCUC-5′ (SEQ ID NO: 263) AAT-868 Target:5′-TGGATTTGGTCAAGGAGCTTGACAGAG-3′ (SEQ ID NO: 461)5′-AUUUGGUCAAGGAGCUUGACAGAGA-3′ (SEQ ID NO: 660)3′-CCUAAACCAGUUCCUCGAACUGUCUCU-5′ (SEQ ID NO: 264) AAT-869 Target:5′-GGATTTGGTCAAGGAGCTTGACAGAGA-3′ (SEQ ID NO: 462)5′-UUUGGUCAAGGAGCUUGACAGAGAC-3′ (SEQ ID NO: 661)3′-CUAAACCAGUUCCUCGAACUGUCUCUG-5′ (SEQ ID NO: 265) AAT-870 Target:5′-GATTTGGTCAAGGAGCTTGACAGAGAC-3′ (SEQ ID NO: 463)5′-UUGGUCAAGGAGCUUGACAGAGACA-3′ (SEQ ID NO: 662)3′-UAAACCAGUUCCUCGAACUGUCUCUGU-5′ (SEQ ID NO: 266) AAT-871 Target:5′-ATTTGGTCAAGGAGCTTGACAGAGACA-3′ (SEQ ID NO: 464)5′-UGGUCAAGGAGCUUGACAGAGACAC-3′ (SEQ ID NO: 663)3′-AAACCAGUUCCUCGAACUGUCUCUGUG-5′ (SEQ ID NO: 267) AAT-872 Target:5′-TTTGGTCAAGGAGCTTGACAGAGACAC-3′ (SEQ ID NO: 465)5′-CAGUUUUUGCUCUGGUGAAUUACAU-3′ (SEQ ID NO: 664)3′-GUGUCAAAAACGAGACCACUUAAUGUA-5′ (SEQ ID NO: 268) AAT-896 Target:5′-CACAGTTTTTGCTCTGGTGAATTACAT-3′ (SEQ ID NO: 466)5′-AGUUUUUGCUCUGGUGAAUUACAUC-3′ (SEQ ID NO: 665)3′-UGUCAAAAACGAGACCACUUAAUGUAG-5′ (SEQ ID NO: 269) AAT-897 Target:5′-ACAGTTTTTGCTCTGGTGAATTACATC-3′ (SEQ ID NO: 467)5′-GUUUUUGCUCUGGUGAAUUACAUCU-3′ (SEQ ID NO: 666)3′-GUCAAAAACGAGACCACUUAAUGUAGA-5′ (SEQ ID NO: 270) AAT-898 Target:5′-CAGTTTTTGCTCTGGTGAATTACATCT-3′ (SEQ ID NO: 468)5′-UUUUUGCUCUGGUGAAUUACAUCUU-3′ (SEQ ID NO: 667)3′-UCAAAAACGAGACCACUUAAUGUAGAA-5′ (SEQ ID NO: 271) AAT-899 Target:5′-AGTTTTTGCTCTGGTGAATTACATCTT-3′ (SEQ ID NO: 469)5′-AAAGGCAAAUGGGAGAGACCCUUUG-3′ (SEQ ID NO: 668)3′-AAUUUCCGUUUACCCUCUCUGGGAAAC-5′ (SEQ ID NO: 272) AAT-928 Target:5′-TTAAAGGCAAATGGGAGAGACCCTTTG-3′ (SEQ ID NO: 470)5′-AAGGCAAAUGGGAGAGACCCUUUGA-3′ (SEQ ID NO: 669)3′-AUUUCCGUUUACCCUCUCUGGGAAACU-5′ (SEQ ID NO: 273) AAT-929 Target:5′-TAAAGGCAAATGGGAGAGACCCTTTGA-3′ (SEQ ID NO: 471)5′-AGGCAAAUGGGAGAGACCCUUUGAA-3′ (SEQ ID NO: 670)3′-UUUCCGUUUACCCUCUCUGGGAAACUU-5′ (SEQ ID NO: 274) AAT-930 Target:5′-AAAGGCAAATGGGAGAGACCCTTTGAA-3′ (SEQ ID NO: 472)5′-GGCAAAUGGGAGAGACCCUUUGAAG-3′ (SEQ ID NO: 671)3′-UUCCGUUUACCCUCUCUGGGAAACUUC-5′ (SEQ ID NO: 275) AAT-931 Target:5′-AAGGCAAATGGGAGAGACCCTTTGAAG-3′ (SEQ ID NO: 473)5′-AGGAAGAGGACUUCCACGUGGACCA-3′ (SEQ ID NO: 672)3′-GCUCCUUCUCCUGAAGGUGCACCUGGU-5′ (SEQ ID NO: 276) AAT-968 Target:5′-CGAGGAAGAGGACTTCCACGTGGACCA-3′ (SEQ ID NO: 474)5′-GGAAGAGGACUUCCACGUGGACCAG-3′ (SEQ ID NO: 673)3′-CUCCUUCUCCUGAAGGUGCACCUGGUC-5′ (SEQ ID NO: 277) AAT-969 Target:5′-GAGGAAGAGGACTTCCACGTGGACCAG-3′ (SEQ ID NO: 475)5′-GAAGAGGACUUCCACGUGGACCAGG-3′ (SEQ ID NO: 674)3′-UCCUUCUCCUGAAGGUGCACCUGGUCC-5′ (SEQ ID NO: 278) AAT-970 Target:5′-AGGAAGAGGACTTCCACGTGGACCAGG-3′ (SEQ ID NO: 476)5′-AAGAGGACUUCCACGUGGACCAGGU-3′ (SEQ ID NO: 675)3′-CCUUCUCCUGAAGGUGCACCUGGUCCA-5′ (SEQ ID NO: 279) AAT-971 Target:5′-GGAAGAGGACTTCCACGTGGACCAGGT-3′ (SEQ ID NO: 477)5′-GAGGACUUCCACGUGGACCAGGUGA-3′ (SEQ ID NO: 676)3′-UUCUCCUGAAGGUGCACCUGGUCCACU-5′ (SEQ ID NO: 280) AAT-973 Target:5′-AAGAGGACTTCCACGTGGACCAGGTGA-3′ (SEQ ID NO: 478)5′-AGGACUUCCACGUGGACCAGGUGAC-3′ (SEQ ID NO: 677)3′-UCUCCUGAAGGUGCACCUGGUCCACUG-5′ (SEQ ID NO: 281) AAT-974 Target:5′-AGAGGACTTCCACGTGGACCAGGTGAC-3′ (SEQ ID NO: 479)5′-GACUUCCACGUGGACCAGGUGACCA-3′ (SEQ ID NO: 678)3′-UCCUGAAGGUGCACCUGGUCCACUGGU-5′ (SEQ ID NO: 282) AAT-976 Target:5′-AGGACTTCCACGTGGACCAGGTGACCA-3′ (SEQ ID NO: 480)5′-GUUUAGGCAUGUUUAACAUCCAGCA-3′ (SEQ ID NO: 679)3′-CGCAAAUCCGUACAAAUUGUAGGUCGU-5′ (SEQ ID NO: 283) AAT-1025 Target:5′-GCGTTTAGGCATGTTTAACATCCAGCA-3′ (SEQ ID NO: 481)5′-UUUAGGCAUGUUUAACAUCCAGCAC-3′ (SEQ ID NO: 680)3′-GCAAAUCCGUACAAAUUGUAGGUCGUG-5′ (SEQ ID NO: 284) AAT-1026 Target:5′-CGTTTAGGCATGTTTAACATCCAGCAC-3′ (SEQ ID NO: 482)5′-GCUGUCCAGCUGGGUGCUGCUGAUG-3′ (SEQ ID NO: 681)3′-UUCGACAGGUCGACCCACGACGACUAC-5′ (SEQ ID NO: 285) AAT-1059 Target:5′-AAGCTGTCCAGCTGGGTGCTGCTGATG-3′ (SEQ ID NO: 483)5′-CUGUCCAGCUGGGUGCUGCUGAUGA-3′ (SEQ ID NO: 682)3′-UCGACAGGUCGACCCACGACGACUACU-5′ (SEQ ID NO: 286) AAT-1060 Target:5′-AGCTGTCCAGCTGGGTGCTGCTGATGA-3′ (SEQ ID NO: 484)5′-CAAUGCCACCGCCAUCUUCUUCCUG-3′ (SEQ ID NO: 683)3′-CCGUUACGGUGGCGGUAGAAGAAGGAC-5′ (SEQ ID NO: 287) AAT-1095 Target:5′-GGCAATGCCACCGCCATCTTCTTCCTG-3′ (SEQ ID NO: 485)5′-AAUGCCACCGCCAUCUUCUUCCUGC-3′ (SEQ ID NO: 684)3′-CGUUACGGUGGCGGUAGAAGAAGGACG-5′ (SEQ ID NO: 288) AAT-1096 Target:5′-GCAATGCCACCGCCATCTTCTTCCTGC-3′ (SEQ ID NO: 486)5′-CCACCGCCAUCUUCUUCCUGCCUGA-3′ (SEQ ID NO: 685)3′-ACGGUGGCGGUAGAAGAAGGACGGACU-5′ (SEQ ID NO: 289) AAT-1100 Target:5′-TGCCACCGCCATCTTCTTCCTGCCTGA-3′ (SEQ ID NO: 487)5′-CACCGCCAUCUUCUUCCUGCCUGAU-3′ (SEQ ID NO: 686)3′-CGGUGGCGGUAGAAGAAGGACGGACUA-5′ (SEQ ID NO: 290) AAT-1101 Target:5′-GCCACCGCCATCTTCTTCCTGCCTGAT-3′ (SEQ ID NO: 488)5′-ACCGCCAUCUUCUUCCUGCCUGAUG-3′ (SEQ ID NO: 687)3′-GGUGGCGGUAGAAGAAGGACGGACUAC-5′ (SEQ ID NO: 291) AAT-1102 Target:5′-CCACCGCCATCTTCTTCCTGCCTGATG-3′ (SEQ ID NO: 489)5′-CCGCCAUCUUCUUCCUGCCUGAUGA-3′ (SEQ ID NO: 688)3′-GUGGCGGUAGAAGAAGGACGGACUACU-5′ (SEQ ID NO: 292) AAT-1103 Target:5′-CACCGCCATCTTCTTCCTGCCTGATGA-3′ (SEQ ID NO: 490)5′-CGCCAUCUUCUUCCUGCCUGAUGAG-3′ (SEQ ID NO: 689)3′-UGGCGGUAGAAGAAGGACGGACUACUC-5′ (SEQ ID NO: 293) AAT-1104 Target:5′-ACCGCCATCTTCTTCCTGCCTGATGAG-3′ (SEQ ID NO: 491)5′-GCCAUCUUCUUCCUGCCUGAUGAGG-3′ (SEQ ID NO: 690)3′-GGCGGUAGAAGAAGGACGGACUACUCC-5′ (SEQ ID NO: 294) AAT-1105 Target:5′-CCGCCATCTTCTTCCTGCCTGATGAGG-3′ (SEQ ID NO: 492)5′-AUCUUCUUCCUGCCUGAUGAGGGGA-3′ (SEQ ID NO: 691)3′-GGUAGAAGAAGGACGGACUACUCCCCU-5′ (SEQ ID NO: 295) AAT-1108 Target:5′-CCATCTTCTTCCTGCCTGATGAGGGGA-3′ (SEQ ID NO: 493)5′-CUUCCUGCCUGAUGAGGGGAAACUA-3′ (SEQ ID NO: 692)3′-AAGAAGGACGGACUACUCCCCUUUGAU-5′ (SEQ ID NO: 296) AAT-1113 Target:5′-TTCTTCCTGCCTGATGAGGGGAAACTA-3′ (SEQ ID NO: 494)5′-UUCCUGCCUGAUGAGGGGAAACUAC-3′ (SEQ ID NO: 693)3′-AGAAGGACGGACUACUCCCCUUUGAUG-5′ (SEQ ID NO: 297) AAT-1114 Target:5′-TCTTCCTGCCTGATGAGGGGAAACTAC-3′ (SEQ ID NO: 495)5′-UCCUGCCUGAUGAGGGGAAACUACA-3′ (SEQ ID NO: 694)3′-GAAGGACGGACUACUCCCCUUUGAUGU-5′ (SEQ ID NO: 298) AAT-1115 Target:5′-CTTCCTGCCTGATGAGGGGAAACTACA-3′ (SEQ ID NO: 496)5′-CCUGCCUGAUGAGGGGAAACUACAG-3′ (SEQ ID NO: 695)3′-AAGGACGGACUACUCCCCUUUGAUGUC-5′ (SEQ ID NO: 299) AAT-1116 Target:5′-TTCCTGCCTGATGAGGGGAAACTACAG-3′ (SEQ ID NO: 497)5′-CUGCCUGAUGAGGGGAAACUACAGC-3′ (SEQ ID NO: 696)3′-AGGACGGACUACUCCCCUUUGAUGUCG-5′ (SEQ ID NO: 300) AAT-1117 Target:5′-TCCTGCCTGATGAGGGGAAACTACAGC-3′ (SEQ ID NO: 498)5′-UGCCUGAUGAGGGGAAACUACAGCA-3′ (SEQ ID NO: 697)3′-GGACGGACUACUCCCCUUUGAUGUCGU-5′ (SEQ ID NO: 301) AAT-1118 Target:5′-CCTGCCTGATGAGGGGAAACTACAGCA-3′ (SEQ ID NO: 499)5′-AGCACCUGGAAAAUGAACUCACCCA-3′ (SEQ ID NO: 698)3′-UGUCGUGGACCUUUUACUUGAGUGGGU-5′ (SEQ ID NO: 302) AAT-1139 Target:5′-ACAGCACCTGGAAAATGAACTCACCCA-3′ (SEQ ID NO: 500)5′-GCACCUGGAAAAUGAACUCACCCAC-3′ (SEQ ID NO: 699)3′-GUCGUGGACCUUUUACUUGAGUGGGUG-5′ (SEQ ID NO: 303) AAT-1140 Target:5′-CAGCACCTGGAAAATGAACTCACCCAC-3′ (SEQ ID NO: 501)5′-CACCUGGAAAAUGAACUCACCCACG-3′ (SEQ ID NO: 700)3′-UCGUGGACCUUUUACUUGAGUGGGUGC-5′ (SEQ ID NO: 304) AAT-1141 Target:5′-AGCACCTGGAAAATGAACTCACCCACG-3′ (SEQ ID NO: 502)5′-ACCUGGAAAAUGAACUCACCCACGA-3′ (SEQ ID NO: 701)3′-CGUGGACCUUUUACUUGAGUGGGUGCU-5′ (SEQ ID NO: 305) AAT-1142 Target:5′-GCACCTGGAAAATGAACTCACCCACGA-3′ (SEQ ID NO: 503)5′-CCUGGAAAAUGAACUCACCCACGAU-3′ (SEQ ID NO: 702)3′-GUGGACCUUUUACUUGAGUGGGUGCUA-5′ (SEQ ID NO: 306) AAT-1143 Target:5′-CACCTGGAAAATGAACTCACCCACGAT-3′ (SEQ ID NO: 504)5′-AUAUCAUCACCAAGUUCCUGGAAAA-3′ (SEQ ID NO: 703)3′-GCUAUAGUAGUGGUUCAAGGACCUUUU-5′ (SEQ ID NO: 307) AAT-1166 Target:5′-CGATATCATCACCAAGTTCCTGGAAAA-3′ (SEQ ID NO: 505)5′-UAUCAUCACCAAGUUCCUGGAAAAU-3′ (SEQ ID NO: 704)3′-CUAUAGUAGUGGUUCAAGGACCUUUUA-5′ (SEQ ID NO: 308) AAT-1167 Target:5′-GATATCATCACCAAGTTCCTGGAAAAT-3′ (SEQ ID NO: 506)5′-AUCAUCACCAAGUUCCUGGAAAAUG-3′ (SEQ ID NO: 705)3′-UAUAGUAGUGGUUCAAGGACCUUUUAC-5′ (SEQ ID NO: 309) AAT-1168 Target:5′-ATATCATCACCAAGTTCCTGGAAAATG-3′ (SEQ ID NO: 507)5′-UCAUCACCAAGUUCCUGGAAAAUGA-3′ (SEQ ID NO: 706)3′-AUAGUAGUGGUUCAAGGACCUUUUACU-5′ (SEQ ID NO: 310) AAT-1169 Target:5′-TATCATCACCAAGTTCCTGGAAAATGA-3′ (SEQ ID NO: 508)5′-CAUCACCAAGUUCCUGGAAAAUGAA-3′ (SEQ ID NO: 707)3′-UAGUAGUGGUUCAAGGACCUUUUACUU-5′ (SEQ ID NO: 311) AAT-1170 Target:5′-ATCATCACCAAGTTCCTGGAAAATGAA-3′ (SEQ ID NO: 509)5′-AUCACCAAGUUCCUGGAAAAUGAAG-3′ (SEQ ID NO: 708)3′-AGUAGUGGUUCAAGGACCUUUUACUUC-5′ (SEQ ID NO: 312) AAT-1171 Target:5′-TCATCACCAAGTTCCTGGAAAATGAAG-3′ (SEQ ID NO: 510)5′-UCACCAAGUUCCUGGAAAAUGAAGA-3′ (SEQ ID NO: 709)3′-GUAGUGGUUCAAGGACCUUUUACUUCU-5′ (SEQ ID NO: 313) AAT-1172 Target:5′-CATCACCAAGTTCCTGGAAAATGAAGA-3′ (SEQ ID NO: 511)5′-CACCAAGUUCCUGGAAAAUGAAGAC-3′ (SEQ ID NO: 710)3′-UAGUGGUUCAAGGACCUUUUACUUCUG-5′ (SEQ ID NO: 314) AAT-1173 Target:5′-ATCACCAAGTTCCTGGAAAATGAAGAC-3′ (SEQ ID NO: 512)5′-ACCAAGUUCCUGGAAAAUGAAGACA-3′ (SEQ ID NO: 711)3′-AGUGGUUCAAGGACCUUUUACUUCUGU-5′ (SEQ ID NO: 315) AAT-1174 Target:5′-TCACCAAGTTCCTGGAAAATGAAGACA-3′ (SEQ ID NO: 513)5′-CCAAGUUCCUGGAAAAUGAAGACAG-3′ (SEQ ID NO: 712)3′-GUGGUUCAAGGACCUUUUACUUCUGUC-5′ (SEQ ID NO: 316) AAT-1175 Target:5′-CACCAAGTTCCTGGAAAATGAAGACAG-3′ (SEQ ID NO: 514)5′-AGGUCUUCAGCAAUGGGGCUGACCU-3′ (SEQ ID NO: 713)3′-AUUCCAGAAGUCGUUACCCCGACUGGA-5′ (SEQ ID NO: 317) AAT-1286 Target:5′-TAAGGTCTTCAGCAATGGGGCTGACCT-3′ (SEQ ID NO: 515)5′-CAAUGGGGCUGACCUCUCCGGGGUC-3′ (SEQ ID NO: 714)3′-UCGUUACCCCGACUGGAGAGGCCCCAG-5′ (SEQ ID NO: 318) AAT-1296 Target:5′-AGCAATGGGGCTGACCTCTCCGGGGTC-3′ (SEQ ID NO: 516)5′-AAUGGGGCUGACCUCUCCGGGGUCA-3′ (SEQ ID NO: 715)3′-CGUUACCCCGACUGGAGAGGCCCCAGU-5′ (SEQ ID NO: 319) AAT-1297 Target:5′-GCAATGGGGCTGACCTCTCCGGGGTCA-3′ (SEQ ID NO: 517)5′-AUGGGGCUGACCUCUCCGGGGUCAC-3′ (SEQ ID NO: 716)3′-GUUACCCCGACUGGAGAGGCCCCAGUG-5′ (SEQ ID NO: 320) AAT-1298 Target:5′-CAATGGGGCTGACCTCTCCGGGGTCAC-3′ (SEQ ID NO: 518)5′-GAGGAGGCACCCCUGAAGCUCUCCA-3′ (SEQ ID NO: 717)3′-GUCUCCUCCGUGGGGACUUCGAGAGGU-5′ (SEQ ID NO: 321) AAT-1324 Target:5′-CAGAGGAGGCACCCCTGAAGCTCTCCA-3′ (SEQ ID NO: 519)5′-GGAGGCACCCCUGAAGCUCUCCAAG-3′ (SEQ ID NO: 718)3′-CUCCUCCGUGGGGACUUCGAGAGGUUC-5′ (SEQ ID NO: 322) AAT-1326 Target:5′-GAGGAGGCACCCCTGAAGCTCTCCAAG-3′ (SEQ ID NO: 520)5′-CUGAAGCUCUCCAAGGCCGUGCAUA-3′ (SEQ ID NO: 719)3′-GGGACUUCGAGAGGUUCCGGCACGUAU-5′ (SEQ ID NO: 323) AAT-1336 Target:5′-CCCTGAAGCTCTCCAAGGCCGTGCATA-3′ (SEQ ID NO: 521)5′-CGUGCAUAAGGCUGUGCUGACCAUC-3′ (SEQ ID NO: 720)3′-CGGCACGUAUUCCGACACGACUGGUAG-5′ (SEQ ID NO: 324) AAT-1353 Target:5′-GCCGTGCATAAGGCTGTGCTGACCATC-3′ (SEQ ID NO: 522)5′-GUGCAUAAGGCUGUGCUGACCAUCG-3′ (SEQ ID NO: 721)3′-GGCACGUAUUCCGACACGACUGGUAGC-5′ (SEQ ID NO: 325) AAT-1354 Target:5′-CCGTGCATAAGGCTGTGCTGACCATCG-3′ (SEQ ID NO: 523)5′-UGCAUAAGGCUGUGCUGACCAUCGA-3′ (SEQ ID NO: 722)3′-GCACGUAUUCCGACACGACUGGUAGCU-5′ (SEQ ID NO: 326) AAT-1355 Target:5′-CGTGCATAAGGCTGTGCTGACCATCGA-3′ (SEQ ID NO: 524)5′-GCAUAAGGCUGUGCUGACCAUCGAC-3′ (SEQ ID NO: 723)3′-CACGUAUUCCGACACGACUGGUAGCUG-5′ (SEQ ID NO: 327) AAT-1356 Target:5′-GTGCATAAGGCTGTGCTGACCATCGAC-3′ (SEQ ID NO: 525)5′-CAUAAGGCUGUGCUGACCAUCGACG-3′ (SEQ ID NO: 724)3′-ACGUAUUCCGACACGACUGGUAGCUGC-5′ (SEQ ID NO: 328) AAT-1357 Target:5′-TGCATAAGGCTGTGCTGACCATCGACG-3′ (SEQ ID NO: 526)5′-AUAAGGCUGUGCUGACCAUCGACGA-3′ (SEQ ID NO: 725)3′-CGUAUUCCGACACGACUGGUAGCUGCU-5′ (SEQ ID NO: 329) AAT-1358 Target:5′-GCATAAGGCTGTGCTGACCATCGACGA-3′ (SEQ ID NO: 527)5′-UAAGGCUGUGCUGACCAUCGACGAG-3′ (SEQ ID NO: 726)3′-GUAUUCCGACACGACUGGUAGCUGCUC-5′ (SEQ ID NO: 330) AAT-1359 Target:5′-CATAAGGCTGTGCTGACCATCGACGAG-3′ (SEQ ID NO: 528)5′-AAGGCUGUGCUGACCAUCGACGAGA-3′ (SEQ ID NO: 727)3′-UAUUCCGACACGACUGGUAGCUGCUCU-5′ (SEQ ID NO: 331) AAT-1360 Target:5′-ATAAGGCTGTGCTGACCATCGACGAGA-3′ (SEQ ID NO: 529)5′-AGGCUGUGCUGACCAUCGACGAGAA-3′ (SEQ ID NO: 728)3′-AUUCCGACACGACUGGUAGCUGCUCUU-5′ (SEQ ID NO: 332) AAT-1361 Target:5′-TAAGGCTGTGCTGACCATCGACGAGAA-3′ (SEQ ID NO: 530)5′-ACUGAAGCUGCUGGGGCCAUGUUUU-3′ (SEQ ID NO: 729)3′-CCUGACUUCGACGACCCCGGUACAAAA-5′ (SEQ ID NO: 333) AAT-1390 Target:5′-GGACTGAAGCTGCTGGGGCCATGTTTT-3′ (SEQ ID NO: 531)5′-CUGAAGCUGCUGGGGCCAUGUUUUU-3′ (SEQ ID NO: 730)3′-CUGACUUCGACGACCCCGGUACAAAAA-5′ (SEQ ID NO: 334) AAT-1391 Target:5′-GACTGAAGCTGCTGGGGCCATGTTTTT-3′ (SEQ ID NO: 532)5′-UGAAGCUGCUGGGGCCAUGUUUUUA-3′ (SEQ ID NO: 731)3′-UGACUUCGACGACCCCGGUACAAAAAU-5′ (SEQ ID NO: 335) AAT-1392 Target:5′-ACTGAAGCTGCTGGGGCCATGTTTTTA-3′ (SEQ ID NO: 533)5′-GAAGCUGCUGGGGCCAUGUUUUUAG-3′ (SEQ ID NO: 732)3′-GACUUCGACGACCCCGGUACAAAAAUC-5′ (SEQ ID NO: 336) AAT-1393 Target:5′-CTGAAGCTGCTGGGGCCATGTTTTTAG-3′ (SEQ ID NO: 534)5′-AAGCUGCUGGGGCCAUGUUUUUAGA-3′ (SEQ ID NO: 733)3′-ACUUCGACGACCCCGGUACAAAAAUCU-5′ (SEQ ID NO: 337) AAT-1394 Target:5′-TGAAGCTGCTGGGGCCATGTTTTTAGA-3′ (SEQ ID NO: 535)5′-AGCUGCUGGGGCCAUGUUUUUAGAG-3′ (SEQ ID NO: 734)3′-CUUCGACGACCCCGGUACAAAAAUCUC-5′ (SEQ ID NO: 338) AAT-1395 Target:5′-GAAGCTGCTGGGGCCATGTTTTTAGAG-3′ (SEQ ID NO: 536)5′-GCCAUGUUUUUAGAGGCCAUACCCA-3′ (SEQ ID NO: 735)3′-CCCGGUACAAAAAUCUCCGGUAUGGGU-5′ (SEQ ID NO: 339) AAT-1405 Target:5′-GGGCCATGTTTTTAGAGGCCATACCCA-3′ (SEQ ID NO: 537)5′-CCAUGUUUUUAGAGGCCAUACCCAU-3′ (SEQ ID NO: 736)3′-CCGGUACAAAAAUCUCCGGUAUGGGUA-5′ (SEQ ID NO: 340) AAT-1406 Target:5′-GGCCATGTTTTTAGAGGCCATACCCAT-3′ (SEQ ID NO: 538)5′-CAUGUUUUUAGAGGCCAUACCCAUG-3′ (SEQ ID NO: 737)3′-CGGUACAAAAAUCUCCGGUAUGGGUAC-5′ (SEQ ID NO: 341) AAT-1407 Target:5′-GCCATGTTTTTAGAGGCCATACCCATG-3′ (SEQ ID NO: 539)5′-AUGUUUUUAGAGGCCAUACCCAUGU-3′ (SEQ ID NO: 738)3′-GGUACAAAAAUCUCCGGUAUGGGUACA-5′ (SEQ ID NO: 342) AAT-1408 Target:5′-CCATGTTTTTAGAGGCCATACCCATGT-3′ (SEQ ID NO: 540)5′-UGUUUUUAGAGGCCAUACCCAUGUC-3′ (SEQ ID NO: 739)3′-GUACAAAAAUCUCCGGUAUGGGUACAG-5′ (SEQ ID NO: 343) AAT-1409 Target:5′-CATGTTTTTAGAGGCCATACCCATGTC-3′ (SEQ ID NO: 541)5′-GUUUUUAGAGGCCAUACCCAUGUCU-3′ (SEQ ID NO: 740)3′-UACAAAAAUCUCCGGUAUGGGUACAGA-5′ (SEQ ID NO: 344) AAT-1410 Target:5′-ATGTTTTTAGAGGCCATACCCATGTCT-3′ (SEQ ID NO: 542)5′-UUUUUAGAGGCCAUACCCAUGUCUA-3′ (SEQ ID NO: 741)3′-ACAAAAAUCUCCGGUAUGGGUACAGAU-5′ (SEQ ID NO: 345) AAT-1411 Target:5′-TGTTTTTAGAGGCCATACCCATGTCTA-3′ (SEQ ID NO: 543)5′-UUUUAGAGGCCAUACCCAUGUCUAU-3′ (SEQ ID NO: 742)3′-CAAAAAUCUCCGGUAUGGGUACAGAUA-5′ (SEQ ID NO: 346) AAT-1412 Target:5′-GTTTTTAGAGGCCATACCCATGTCTAT-3′ (SEQ ID NO: 544)5′-UUUAGAGGCCAUACCCAUGUCUAUC-3′ (SEQ ID NO: 743)3′-AAAAAUCUCCGGUAUGGGUACAGAUAG-5′ (SEQ ID NO: 347) AAT-1413 Target:5′-TTTTTAGAGGCCATACCCATGTCTATC-3′ (SEQ ID NO: 545)5′-UUAGAGGCCAUACCCAUGUCUAUCC-3′ (SEQ ID NO: 744)3′-AAAAUCUCCGGUAUGGGUACAGAUAGG-5′ (SEQ ID NO: 348) AAT-1414 Target:5′-TTTTAGAGGCCATACCCATGTCTATCC-3′ (SEQ ID NO: 546)5′-UAGAGGCCAUACCCAUGUCUAUCCC-3′ (SEQ ID NO: 745)3′-AAAUCUCCGGUAUGGGUACAGAUAGGG-5′ (SEQ ID NO: 349) AAT-1415 Target:5′-TTTAGAGGCCATACCCATGTCTATCCC-3′ (SEQ ID NO: 547)5′-AGAGGCCAUACCCAUGUCUAUCCCC-3′ (SEQ ID NO: 746)3′-AAUCUCCGGUAUGGGUACAGAUAGGGG-5′ (SEQ ID NO: 350) AAT-1416 Target:5′-TTAGAGGCCATACCCATGTCTATCCCC-3′ (SEQ ID NO: 548)5′-GUUCAACAAACCCUUUGUCUUCUUA-3′ (SEQ ID NO: 747)3′-UUCAAGUUGUUUGGGAAACAGAAGAAU-5′ (SEQ ID NO: 351) AAT-1452 Target:5′-AAGTTCAACAAACCCTTTGTCTTCTTA-3′ (SEQ ID NO: 549)5′-UUCAACAAACCCUUUGUCUUCUUAA-3′ (SEQ ID NO: 748)3′-UCAAGUUGUUUGGGAAACAGAAGAAUU-5′ (SEQ ID NO: 352) AAT-1453 Target:5′-AGTTCAACAAACCCTTTGTCTTCTTAA-3′ (SEQ ID NO: 550)5′-UCAACAAACCCUUUGUCUUCUUAAU-3′ (SEQ ID NO: 749)3′-CAAGUUGUUUGGGAAACAGAAGAAUUA-5′ (SEQ ID NO: 353) AAT-1454 Target:5′-GTTCAACAAACCCTTTGTCTTCTTAAT-3′ (SEQ ID NO: 551)5′-CAACAAACCCUUUGUCUUCUUAAUG-3′ (SEQ ID NO: 750)3′-AAGUUGUUUGGGAAACAGAAGAAUUAC-5′ (SEQ ID NO: 354) AAT-1455 Target:5′-TTCAACAAACCCTTTGTCTTCTTAATG-3′ (SEQ ID NO: 552)5′-AACAAACCCUUUGUCUUCUUAAUGA-3′ (SEQ ID NO: 751)3′-AGUUGUUUGGGAAACAGAAGAAUUACU-5′ (SEQ ID NO: 355) AAT-1456 Target:5′-TCAACAAACCCTTTGTCTTCTTAATGA-3′ (SEQ ID NO: 553)5′-ACAAACCCUUUGUCUUCUUAAUGAU-3′ (SEQ ID NO: 752)3′-GUUGUUUGGGAAACAGAAGAAUUACUA-5′ (SEQ ID NO: 356) AAT-1457 Target:5′-CAACAAACCCTTTGTCTTCTTAATGAT-3′ (SEQ ID NO: 554)5′-CAAACCCUUUGUCUUCUUAAUGAUU-3′ (SEQ ID NO: 753)3′-UUGUUUGGGAAACAGAAGAAUUACUAA-5′ (SEQ ID NO: 357) AAT-1458 Target:5′-AACAAACCCTTTGTCTTCTTAATGATT-3′ (SEQ ID NO: 555)5′-AAACCCUUUGUCUUCUUAAUGAUUG-3′ (SEQ ID NO: 754)3′-UGUUUGGGAAACAGAAGAAUUACUAAC-5′ (SEQ ID NO: 358) AAT-1459 Target:5′-ACAAACCCTTTGTCTTCTTAATGATTG-3′ (SEQ ID NO: 556)5′-AACCCUUUGUCUUCUUAAUGAUUGA-3′ (SEQ ID NO: 755)3′-GUUUGGGAAACAGAAGAAUUACUAACU-5′ (SEQ ID NO: 359) AAT-1460 Target:5′-CAAACCCTTTGTCTTCTTAATGATTGA-3′ (SEQ ID NO: 557)5′-AAUACCAAGUCUCCCCUCUUCAUGG-3′ (SEQ ID NO: 756)3′-UUUUAUGGUUCAGAGGGGAGAAGUACC-5′ (SEQ ID NO: 360) AAT-1489 Target:5′-AAAATACCAAGTCTCCCCTCTTCATGG-3′ (SEQ ID NO: 558)5′-AUACCAAGUCUCCCCUCUUCAUGGG-3′ (SEQ ID NO: 757)3′-UUUAUGGUUCAGAGGGGAGAAGUACCC-5′ (SEQ ID NO: 361) AAT-1490 Target:5′-AAATACCAAGTCTCCCCTCTTCATGGG-3′ (SEQ ID NO: 559)5′-UACCAAGUCUCCCCUCUUCAUGGGA-3′ (SEQ ID NO: 758)3′-UUAUGGUUCAGAGGGGAGAAGUACCCU-5′ (SEQ ID NO: 362) AAT-1491 Target:5′-AATACCAAGTCTCCCCTCTTCATGGGA-3′ (SEQ ID NO: 560)5′-ACCAAGUCUCCCCUCUUCAUGGGAA-3′ (SEQ ID NO: 759)3′-UAUGGUUCAGAGGGGAGAAGUACCCUU-5′ (SEQ ID NO: 363) AAT-1492 Target:5′-ATACCAAGTCTCCCCTCTTCATGGGAA-3′ (SEQ ID NO: 561)5′-CCAAGUCUCCCCUCUUCAUGGGAAA-3′ (SEQ ID NO: 760)3′-AUGGUUCAGAGGGGAGAAGUACCCUUU-5′ (SEQ ID NO: 364) AAT-1493 Target:5′-TACCAAGTCTCCCCTCTTCATGGGAAA-3′ (SEQ ID NO: 562)5′-CAAGUCUCCCCUCUUCAUGGGAAAA-3′ (SEQ ID NO: 761)3′-UGGUUCAGAGGGGAGAAGUACCCUUUU-5′ (SEQ ID NO: 365) AAT-1494 Target:5′-ACCAAGTCTCCCCTCTTCATGGGAAAA-3′ (SEQ ID NO: 563)5′-AAGUCUCCCCUCUUCAUGGGAAAAG-3′ (SEQ ID NO: 762)3′-GGUUCAGAGGGGAGAAGUACCCUUUUC-5′ (SEQ ID NO: 366) AAT-1495 Target:5′-CCAAGTCTCCCCTCTTCATGGGAAAAG-3′ (SEQ ID NO: 564)5′-AGUCUCCCCUCUUCAUGGGAAAAGU-3′ (SEQ ID NO: 763)3′-GUUCAGAGGGGAGAAGUACCCUUUUCA-5′ (SEQ ID NO: 367) AAT-1496 Target:5′-CAAGTCTCCCCTCTTCATGGGAAAAGT-3′ (SEQ ID NO: 565)5′-GUCUCCCCUCUUCAUGGGAAAAGUG-3′ (SEQ ID NO: 764)3′-UUCAGAGGGGAGAAGUACCCUUUUCAC-5′ (SEQ ID NO: 368) AAT-1497 Target:5′-AAGTCTCCCCTCTTCATGGGAAAAGTG-3′ (SEQ ID NO: 566)5′-CUCCCCUCUUCAUGGGAAAAGUGGU-3′ (SEQ ID NO: 765)3′-CAGAGGGGAGAAGUACCCUUUUCACCA-5′ (SEQ ID NO: 369) AAT-1499 Target:5′-GTCTCCCCTCTTCATGGGAAAAGTGGT-3′ (SEQ ID NO: 567)5′-CCCCUCUUCAUGGGAAAAGUGGUGA-3′ (SEQ ID NO: 766)3′-GAGGGGAGAAGUACCCUUUUCACCACU-5′ (SEQ ID NO: 370) AAT-1501 Target:5′-CTCCCCTCTTCATGGGAAAAGTGGTGA-3′ (SEQ ID NO: 568)5′-CCCUCUUCAUGGGAAAAGUGGUGAA-3′ (SEQ ID NO: 767)3′-AGGGGAGAAGUACCCUUUUCACCACUU-5′ (SEQ ID NO: 371) AAT-1502 Target:5′-TCCCCTCTTCATGGGAAAAGTGGTGAA-3′ (SEQ ID NO: 569)5′-CCUCUUCAUGGGAAAAGUGGUGAAU-3′ (SEQ ID NO: 768)3′-GGGGAGAAGUACCCUUUUCACCACUUA-5′ (SEQ ID NO: 372) AAT-1503 Target:5′-CCCCTCTTCATGGGAAAAGTGGTGAAT-3′ (SEQ ID NO: 570)5′-CUCUUCAUGGGAAAAGUGGUGAAUC-3′ (SEQ ID NO: 769)3′-GGGAGAAGUACCCUUUUCACCACUUAG-5′ (SEQ ID NO: 373) AAT-1504 Target:5′-CCCTCTTCATGGGAAAAGTGGTGAATC-3′ (SEQ ID NO: 571)5′-UCUUCAUGGGAAAAGUGGUGAAUCC-3′ (SEQ ID NO: 770)3′-GGAGAAGUACCCUUUUCACCACUUAGG-5′ (SEQ ID NO: 374) AAT-1505 Target:5′-CCTCTTCATGGGAAAAGTGGTGAATCC-3′ (SEQ ID NO: 572)5′-CUUCAUGGGAAAAGUGGUGAAUCCC-3′ (SEQ ID NO: 771)3′-GAGAAGUACCCUUUUCACCACUUAGGG-5′ (SEQ ID NO: 375) AAT-1506 Target:5′-CTCTTCATGGGAAAAGTGGTGAATCCC-3′ (SEQ ID NO: 573)5′-UUCAUGGGAAAAGUGGUGAAUCCCA-3′ (SEQ ID NO: 772)3′-AGAAGUACCCUUUUCACCACUUAGGGU-5′ (SEQ ID NO: 376) AAT-1507 Target:5′-TCTTCATGGGAAAAGTGGTGAATCCCA-3′ (SEQ ID NO: 574)5′-UCAUGGGAAAAGUGGUGAAUCCCAC-3′ (SEQ ID NO: 773)3′-GAAGUACCCUUUUCACCACUUAGGGUG-5′ (SEQ ID NO: 377) AAT-1508 Target:5′-CTTCATGGGAAAAGTGGTGAATCCCAC-3′ (SEQ ID NO: 575)5′-CAUGGGAAAAGUGGUGAAUCCCACC-3′ (SEQ ID NO: 774)3′-AAGUACCCUUUUCACCACUUAGGGUGG-5′ (SEQ ID NO: 378) AAT-1509 Target:5′-TTCATGGGAAAAGTGGTGAATCCCACC-3′ (SEQ ID NO: 576)5′-AUGGGAAAAGUGGUGAAUCCCACCC-3′ (SEQ ID NO: 775)3′-AGUACCCUUUUCACCACUUAGGGUGGG-5′ (SEQ ID NO: 379) AAT-1510 Target:5′-TCATGGGAAAAGTGGTGAATCCCACCC-3′ (SEQ ID NO: 577)5′-UGGGAAAAGUGGUGAAUCCCACCCA-3′ (SEQ ID NO: 776)3′-GUACCCUUUUCACCACUUAGGGUGGGU-5′ (SEQ ID NO: 380) AAT-1511 Target:5′-CATGGGAAAAGTGGTGAATCCCACCCA-3′ (SEQ ID NO: 578)5′-GGGAAAAGUGGUGAAUCCCACCCAA-3′ (SEQ ID NO: 777)3′-UACCCUUUUCACCACUUAGGGUGGGUU-5′ (SEQ ID NO: 381) AAT-1512 Target:5′-ATGGGAAAAGTGGTGAATCCCACCCAA-3′ (SEQ ID NO: 579)5′-GGAAAAGUGGUGAAUCCCACCCAAA-3′ (SEQ ID NO: 778)3′-ACCCUUUUCACCACUUAGGGUGGGUUU-5′ (SEQ ID NO: 382) AAT-1513 Target:5′-TGGGAAAAGTGGTGAATCCCACCCAAA-3′ (SEQ ID NO: 580)5′-GAAAAGUGGUGAAUCCCACCCAAAA-3′ (SEQ ID NO: 779)3′-CCCUUUUCACCACUUAGGGUGGGUUUU-5′ (SEQ ID NO: 383) AAT-1514 Target:5′-GGGAAAAGTGGTGAATCCCACCCAAAA-3′ (SEQ ID NO: 581)5′-AAAAGUGGUGAAUCCCACCCAAAAA-3′ (SEQ ID NO: 780)3′-CCUUUUCACCACUUAGGGUGGGUUUUU-5′ (SEQ ID NO: 384) AAT-1515 Target:5′-GGAAAAGTGGTGAATCCCACCCAAAAA-3′ (SEQ ID NO: 582)5′-AAAGUGGUGAAUCCCACCCAAAAAU-3′ (SEQ ID NO: 781)3′-CUUUUCACCACUUAGGGUGGGUUUUUA-5′ (SEQ ID NO: 385) AAT-1516 Target:5′-GAAAAGTGGTGAATCCCACCCAAAAAT-3′ (SEQ ID NO: 583)5′-AAGUGGUGAAUCCCACCCAAAAAUA-3′ (SEQ ID NO: 782)3′-UUUUCACCACUUAGGGUGGGUUUUUAU-5′ (SEQ ID NO: 386) AAT-1517 Target:5′-AAAAGTGGTGAATCCCACCCAAAAATA-3′ (SEQ ID NO: 584)5′-CGAUAGUUCAAAAUGGUGAAAUUAG-3′ (SEQ ID NO: 783)3′-AAGCUAUCAAGUUUUACCACUUUAAUC-5′ (SEQ ID NO: 387) AAT-2872 Target:5′-TTCGATAGTTCAAAATGGTGAAATTAG-3′ (SEQ ID NO: 585)5′-CAAAAUGGUGAAAUUAGCAAUUCUA-3′ (SEQ ID NO: 784)3′-AAGUUUUACCACUUUAAUCGUUAAGAU-5′ (SEQ ID NO: 388) AAT-2880 Target:5′-TTCAAAATGGTGAAATTAGCAATTCTA-3′ (SEQ ID NO: 586)5′-UUGGUAUGAUGUUCAAGUUAGAUAA-3′ (SEQ ID NO: 785)3′-UCAACCAUACUACAAGUUCAAUCUAUU-5′ (SEQ ID NO: 389) AAT-3167 Target:5′-AGTTGGTATGATGTTCAAGTTAGATAA-3′ (SEQ ID NO: 587)5′-GGUAUGAUGUUCAAGUUAGAUAACA-3′ (SEQ ID NO: 786)3′-AACCAUACUACAAGUUCAAUCUAUUGU-5′ (SEQ ID NO: 390) AAT-3169 Target:5′-TTGGTATGATGTTCAAGTTAGATAACA-3′ (SEQ ID NO: 588)5′-GUAUGAUGUUCAAGUUAGAUAACAA-3′ (SEQ ID NO: 787)3′-ACCAUACUACAAGUUCAAUCUAUUGUU-5′ (SEQ ID NO: 391) AAT-3170 Target:5′-TGGTATGATGTTCAAGTTAGATAACAA-3′ (SEQ ID NO: 589)5′-AUGAUGUUCAAGUUAGAUAACAAAA-3′ (SEQ ID NO: 788)3′-CAUACUACAAGUUCAAUCUAUUGUUUU-5′ (SEQ ID NO: 392) AAT-3172 Target:5′-GTATGATGTTCAAGTTAGATAACAAAA-3′ (SEQ ID NO: 590)5′-AUGUUCAAGUUAGAUAACAAAAUGU-3′ (SEQ ID NO: 789)3′-ACUACAAGUUCAAUCUAUUGUUUUACA-5′ (SEQ ID NO: 393) AAT-3175 Target:5′-TGATGTTCAAGTTAGATAACAAAATGT-3′ (SEQ ID NO: 591)5′-CAAGUUAGAUAACAAAAUGUUUAUA-3′ (SEQ ID NO: 790)3′-AAGUUCAAUCUAUUGUUUUACAAAUAU-5′ (SEQ ID NO: 394) AAT-3180 Target:5′-TTCAAGTTAGATAACAAAATGTTTATA-3′ (SEQ ID NO: 592)5′-AAGUUAGAUAACAAAAUGUUUAUAC-3′ (SEQ ID NO: 791)3′-AGUUCAAUCUAUUGUUUUACAAAUAUG-5′ (SEQ ID NO: 395) AAT-3181 Target:5′-TCAAGTTAGATAACAAAATGTTTATAC-3′ (SEQ ID NO: 593)5′-AGUUAGAUAACAAAAUGUUUAUACC-3′ (SEQ ID NO: 792)3′-GUUCAAUCUAUUGUUUUACAAAUAUGG-5′ (SEQ ID NO: 396) AAT-3182 Target:5′-CAAGTTAGATAACAAAATGTTTATACC-3′ (SEQ ID NO: 594)

TABLE 4 DsiRNA Target Sequences (21 mers) in α-1 antitrypsin mRNAAAT-395 21 nt Target: 5′-UACAUCCCACCAUGAUCAGGA-3′ (SEQ ID NO: 793)AAT-475 21 nt Target: 5′-GCCAGCUGGCACACCAGUCCA-3′ (SEQ ID NO: 794)AAT-477 21 nt Target: 5′-CAGCUGGCACACCAGUCCAAC-3′ (SEQ ID NO: 795)AAT-480 21 nt Target: 5′-CUGGCACACCAGUCCAACAGC-3′ (SEQ ID NO: 796)AAT-481 21 nt Target: 5′-UGGCACACCAGUCCAACAGCA-3′ (SEQ ID NO: 797)AAT-482 21 nt Target: 5′-GGCACACCAGUCCAACAGCAC-3′ (SEQ ID NO: 798)AAT-483 21 nt Target: 5′-GCACACCAGUCCAACAGCACC-3′ (SEQ ID NO: 799)AAT-484 21 nt Target: 5′-CACACCAGUCCAACAGCACCA-3′ (SEQ ID NO: 800)AAT-500 21 nt Target: 5′-CACCAAUAUCUUCUUCUCCCC-3′ (SEQ ID NO: 801)AAT-501 21 nt Target: 5′-ACCAAUAUCUUCUUCUCCCCA-3′ (SEQ ID NO: 802)AAT-502 21 nt Target: 5′-CCAAUAUCUUCUUCUCCCCAG-3′ (SEQ ID NO: 803)AAT-503 21 nt Target: 5′-CAAUAUCUUCUUCUCCCCAGU-3′ (SEQ ID NO: 804)AAT-504 21 nt Target: 5′-AAUAUCUUCUUCUCCCCAGUG-3′ (SEQ ID NO: 805)AAT-505 21 nt Target: 5′-AUAUCUUCUUCUCCCCAGUGA-3′ (SEQ ID NO: 806)AAT-506 21 nt Target: 5′-UAUCUUCUUCUCCCCAGUGAG-3′ (SEQ ID NO: 807)AAT-507 21 nt Target: 5′-AUCUUCUUCUCCCCAGUGAGC-3′ (SEQ ID NO: 808)AAT-508 21 nt Target: 5′-UCUUCUUCUCCCCAGUGAGCA-3′ (SEQ ID NO: 809)AAT-509 21 nt Target: 5′-CUUCUUCUCCCCAGUGAGCAU-3′ (SEQ ID NO: 810)AAT-510 21 nt Target: 5′-UUCUUCUCCCCAGUGAGCAUC-3′ (SEQ ID NO: 811)AAT-512 21 nt Target: 5′-CUUCUCCCCAGUGAGCAUCGC-3′ (SEQ ID NO: 812)AAT-513 21 nt Target: 5′-UUCUCCCCAGUGAGCAUCGCU-3′ (SEQ ID NO: 813)AAT-515 21 nt Target: 5′-CUCCCCAGUGAGCAUCGCUAC-3′ (SEQ ID NO: 814)AAT-532 21 nt Target: 5′-CUACAGCCUUUGCAAUGCUCU-3′ (SEQ ID NO: 815)AAT-540 21 nt Target: 5′-UUUGCAAUGCUCUCCCUGGGG-3′ (SEQ ID NO: 816)AAT-581 21 nt Target: 5′-UGAAAUCCUGGAGGGCCUGAA-3′ (SEQ ID NO: 817)AAT-582 21 nt Target: 5′-GAAAUCCUGGAGGGCCUGAAU-3′ (SEQ ID NO: 818)AAT-583 21 nt Target: 5′-AAAUCCUGGAGGGCCUGAAUU-3′ (SEQ ID NO: 819)AAT-585 21 nt Target: 5′-AUCCUGGAGGGCCUGAAUUUC-3′ (SEQ ID NO: 820)AAT-586 21 nt Target: 5′-UCCUGGAGGGCCUGAAUUUCA-3′ (SEQ ID NO: 821)AAT-587 21 nt Target: 5′-CCUGGAGGGCCUGAAUUUCAA-3′ (SEQ ID NO: 822)AAT-634 21 nt Target: 5′-UCCAUGAAGGCUUCCAGGAAC-3′ (SEQ ID NO: 823)AAT-637 21 nt Target: 5′-AUGAAGGCUUCCAGGAACUCC-3′ (SEQ ID NO: 824)AAT-638 21 nt Target: 5′-UGAAGGCUUCCAGGAACUCCU-3′ (SEQ ID NO: 825)AAT-671 21 nt Target: 5′-CCAGCCAGACAGCCAGCUCCA-3′ (SEQ ID NO: 826)AAT-673 21 nt Target: 5′-AGCCAGACAGCCAGCUCCAGC-3′ (SEQ ID NO: 827)AAT-675 21 nt Target: 5′-CCAGACAGCCAGCUCCAGCUG-3′ (SEQ ID NO: 828)AAT-676 21 nt Target: 5′-CAGACAGCCAGCUCCAGCUGA-3′ (SEQ ID NO: 829)AAT-734 21 nt Target: 5′-GCUAGUGGAUAAGUUUUUGGA-3′ (SEQ ID NO: 830)AAT-735 21 nt Target: 5′-CUAGUGGAUAAGUUUUUGGAG-3′ (SEQ ID NO: 831)AAT-736 21 nt Target: 5′-UAGUGGAUAAGUUUUUGGAGG-3′ (SEQ ID NO: 832)AAT-737 21 nt Target: 5′-AGUGGAUAAGUUUUUGGAGGA-3′ (SEQ ID NO: 833)AAT-738 21 nt Target: 5′-GUGGAUAAGUUUUUGGAGGAU-3′ (SEQ ID NO: 834)AAT-739 21 nt Target: 5′-UGGAUAAGUUUUUGGAGGAUG-3′ (SEQ ID NO: 835)AAT-740 21 nt Target: 5′-GGAUAAGUUUUUGGAGGAUGU-3′ (SEQ ID NO: 836)AAT-767 21 nt Target: 5′-GUUGUACCACUCAGAAGCCUU-3′ (SEQ ID NO: 837)AAT-768 21 nt Target: 5′-UUGUACCACUCAGAAGCCUUC-3′ (SEQ ID NO: 838)AAT-850 21 nt Target: 5′-GUACUCAAGGGAAAAUUGUGG-3′ (SEQ ID NO: 839)AAT-851 21 nt Target: 5′-UACUCAAGGGAAAAUUGUGGA-3′ (SEQ ID NO: 840)AAT-852 21 nt Target: 5′-ACUCAAGGGAAAAUUGUGGAU-3′ (SEQ ID NO: 841)AAT-853 21 nt Target: 5′-CUCAAGGGAAAAUUGUGGAUU-3′ (SEQ ID NO: 842)AAT-854 21 nt Target: 5′-UCAAGGGAAAAUUGUGGAUUU-3′ (SEQ ID NO: 843)AAT-855 21 nt Target: 5′-CAAGGGAAAAUUGUGGAUUUG-3′ (SEQ ID NO: 844)AAT-856 21 nt Target: 5′-AAGGGAAAAUUGUGGAUUUGG-3′ (SEQ ID NO: 845)AAT-857 21 nt Target: 5′-AGGGAAAAUUGUGGAUUUGGU-3′ (SEQ ID NO: 846)AAT-858 21 nt Target: 5′-GGGAAAAUUGUGGAUUUGGUC-3′ (SEQ ID NO: 847)AAT-859 21 nt Target: 5′-GGAAAAUUGUGGAUUUGGUCA-3′ (SEQ ID NO: 848)AAT-860 21 nt Target: 5′-GAAAAUUGUGGAUUUGGUCAA-3′ (SEQ ID NO: 849)AAT-861 21 nt Target: 5′-AAAAUUGUGGAUUUGGUCAAG-3′ (SEQ ID NO: 850)AAT-862 21 nt Target: 5′-AAAUUGUGGAUUUGGUCAAGG-3′ (SEQ ID NO: 851)AAT-863 21 nt Target: 5′-AAUUGUGGAUUUGGUCAAGGA-3′ (SEQ ID NO: 852)AAT-864 21 nt Target: 5′-AUUGUGGAUUUGGUCAAGGAG-3′ (SEQ ID NO: 853)AAT-865 21 nt Target: 5′-UUGUGGAUUUGGUCAAGGAGC-3′ (SEQ ID NO: 854)AAT-866 21 nt Target: 5′-UGUGGAUUUGGUCAAGGAGCU-3′ (SEQ ID NO: 855)AAT-867 21 nt Target: 5′-GUGGAUUUGGUCAAGGAGCUU-3′ (SEQ ID NO: 856)AAT-868 21 nt Target: 5′-UGGAUUUGGUCAAGGAGCUUG-3′ (SEQ ID NO: 857)AAT-869 21 nt Target: 5′-GGAUUUGGUCAAGGAGCUUGA-3′ (SEQ ID NO: 858)AAT-870 21 nt Target: 5′-GAUUUGGUCAAGGAGCUUGAC-3′ (SEQ ID NO: 859)AAT-871 21 nt Target: 5′-AUUUGGUCAAGGAGCUUGACA-3′ (SEQ ID NO: 860)AAT-872 21 nt Target: 5′-UUUGGUCAAGGAGCUUGACAG-3′ (SEQ ID NO: 861)AAT-896 21 nt Target: 5′-CACAGUUUUUGCUCUGGUGAA-3′ (SEQ ID NO: 862)AAT-897 21 nt Target: 5′-ACAGUUUUUGCUCUGGUGAAU-3′ (SEQ ID NO: 863)AAT-898 21 nt Target: 5′-CAGUUUUUGCUCUGGUGAAUU-3′ (SEQ ID NO: 864)AAT-899 21 nt Target: 5′-AGUUUUUGCUCUGGUGAAUUA-3′ (SEQ ID NO: 865)AAT-928 21 nt Target: 5′-UUAAAGGCAAAUGGGAGAGAC-3′ (SEQ ID NO: 866)AAT-929 21 nt Target: 5′-UAAAGGCAAAUGGGAGAGACC-3′ (SEQ ID NO: 867)AAT-930 21 nt Target: 5′-AAAGGCAAAUGGGAGAGACCC-3′ (SEQ ID NO: 868)AAT-931 21 nt Target: 5′-AAGGCAAAUGGGAGAGACCCU-3′ (SEQ ID NO: 869)AAT-968 21 nt Target: 5′-CGAGGAAGAGGACUUCCACGU-3′ (SEQ ID NO: 870)AAT-969 21 nt Target: 5′-GAGGAAGAGGACUUCCACGUG-3′ (SEQ ID NO: 871)AAT-970 21 nt Target: 5′-AGGAAGAGGACUUCCACGUGG-3′ (SEQ ID NO: 872)AAT-971 21 nt Target: 5′-GGAAGAGGACUUCCACGUGGA-3′ (SEQ ID NO: 873)AAT-973 21 nt Target: 5′-AAGAGGACUUCCACGUGGACC-3′ (SEQ ID NO: 874)AAT-974 21 nt Target: 5′-AGAGGACUUCCACGUGGACCA-3′ (SEQ ID NO: 875)AAT-976 21 nt Target: 5′-AGGACUUCCACGUGGACCAGG-3′ (SEQ ID NO: 876)AAT-1025 21 nt Target: 5′-GCGUUUAGGCAUGUUUAACAU-3′ (SEQ ID NO: 877)AAT-1026 21 nt Target: 5′-CGUUUAGGCAUGUUUAACAUC-3′ (SEQ ID NO: 878)AAT-1059 21 nt Target: 5′-AAGCUGUCCAGCUGGGUGCUG-3′ (SEQ ID NO: 879)AAT-1060 21 nt Target: 5′-AGCUGUCCAGCUGGGUGCUGC-3′ (SEQ ID NO: 880)AAT-1095 21 nt Target: 5′-GGCAAUGCCACCGCCAUCUUC-3′ (SEQ ID NO: 881)AAT-1096 21 nt Target: 5′-GCAAUGCCACCGCCAUCUUCU-3′ (SEQ ID NO: 882)AAT-1100 21 nt Target: 5′-UGCCACCGCCAUCUUCUUCCU-3′ (SEQ ID NO: 883)AAT-1101 21 nt Target: 5′-GCCACCGCCAUCUUCUUCCUG-3′ (SEQ ID NO: 884)AAT-1102 21 nt Target: 5′-CCACCGCCAUCUUCUUCCUGC-3′ (SEQ ID NO: 885)AAT-1103 21 nt Target: 5′-CACCGCCAUCUUCUUCCUGCC-3′ (SEQ ID NO: 886)AAT-1104 21 nt Target: 5′-ACCGCCAUCUUCUUCCUGCCU-3′ (SEQ ID NO: 887)AAT-1105 21 nt Target: 5′-CCGCCAUCUUCUUCCUGCCUG-3′ (SEQ ID NO: 888)AAT-1108 21 nt Target: 5′-CCAUCUUCUUCCUGCCUGAUG-3′ (SEQ ID NO: 889)AAT-1113 21 nt Target: 5′-UUCUUCCUGCCUGAUGAGGGG-3′ (SEQ ID NO: 890)AAT-1114 21 nt Target: 5′-UCUUCCUGCCUGAUGAGGGGA-3′ (SEQ ID NO: 891)AAT-1115 21 nt Target: 5′-CUUCCUGCCUGAUGAGGGGAA-3′ (SEQ ID NO: 892)AAT-1116 21 nt Target: 5′-UUCCUGCCUGAUGAGGGGAAA-3′ (SEQ ID NO: 893)AAT-1117 21 nt Target: 5′-UCCUGCCUGAUGAGGGGAAAC-3′ (SEQ ID NO: 894)AAT-1118 21 nt Target: 5′-CCUGCCUGAUGAGGGGAAACU-3′ (SEQ ID NO: 895)AAT-1139 21 nt Target: 5′-ACAGCACCUGGAAAAUGAACU-3′ (SEQ ID NO: 896)AAT-1140 21 nt Target: 5′-CAGCACCUGGAAAAUGAACUC-3′ (SEQ ID NO: 897)AAT-1141 21 nt Target: 5′-AGCACCUGGAAAAUGAACUCA-3′ (SEQ ID NO: 898)AAT-1142 21 nt Target: 5′-GCACCUGGAAAAUGAACUCAC-3′ (SEQ ID NO: 899)AAT-1143 21 nt Target: 5′-CACCUGGAAAAUGAACUCACC-3′ (SEQ ID NO: 900)AAT-1166 21 nt Target: 5′-CGAUAUCAUCACCAAGUUCCU-3′ (SEQ ID NO: 901)AAT-1167 21 nt Target: 5′-GAUAUCAUCACCAAGUUCCUG-3′ (SEQ ID NO: 902)AAT-1168 21 nt Target: 5′-AUAUCAUCACCAAGUUCCUGG-3′ (SEQ ID NO: 903)AAT-1169 21 nt Target: 5′-UAUCAUCACCAAGUUCCUGGA-3′ (SEQ ID NO: 904)AAT-1170 21 nt Target: 5′-AUCAUCACCAAGUUCCUGGAA-3′ (SEQ ID NO: 905)AAT-1171 21 nt Target: 5′-UCAUCACCAAGUUCCUGGAAA-3′ (SEQ ID NO: 906)AAT-1172 21 nt Target: 5′-CAUCACCAAGUUCCUGGAAAA-3′ (SEQ ID NO: 907)AAT-1173 21 nt Target: 5′-AUCACCAAGUUCCUGGAAAAU-3′ (SEQ ID NO: 908)AAT-1174 21 nt Target: 5′-UCACCAAGUUCCUGGAAAAUG-3′ (SEQ ID NO: 909)AAT-1175 21 nt Target: 5′-CACCAAGUUCCUGGAAAAUGA-3′ (SEQ ID NO: 910)AAT-1286 21 nt Target: 5′-UAAGGUCUUCAGCAAUGGGGC-3′ (SEQ ID NO: 911)AAT-1296 21 nt Target: 5′-AGCAAUGGGGCUGACCUCUCC-3′ (SEQ ID NO: 912)AAT-1297 21 nt Target: 5′-GCAAUGGGGCUGACCUCUCCG-3′ (SEQ ID NO: 913)AAT-1298 21 nt Target: 5′-CAAUGGGGCUGACCUCUCCGG-3′ (SEQ ID NO: 914)AAT-1324 21 nt Target: 5′-CAGAGGAGGCACCCCUGAAGC-3′ (SEQ ID NO: 915)AAT-1326 21 nt Target: 5′-GAGGAGGCACCCCUGAAGCUC-3′ (SEQ ID NO: 916)AAT-1336 21 nt Target: 5′-CCCUGAAGCUCUCCAAGGCCG-3′ (SEQ ID NO: 917)AAT-1353 21 nt Target: 5′-GCCGUGCAUAAGGCUGUGCUG-3′ (SEQ ID NO: 918)AAT-1354 21 nt Target: 5′-CCGUGCAUAAGGCUGUGCUGA-3′ (SEQ ID NO: 919)AAT-1355 21 nt Target: 5′-CGUGCAUAAGGCUGUGCUGAC-3′ (SEQ ID NO: 920)AAT-1356 21 nt Target: 5′-GUGCAUAAGGCUGUGCUGACC-3′ (SEQ ID NO: 921)AAT-1357 21 nt Target: 5′-UGCAUAAGGCUGUGCUGACCA-3′ (SEQ ID NO: 922)AAT-1358 21 nt Target: 5′-GCAUAAGGCUGUGCUGACCAU-3′ (SEQ ID NO: 923)AAT-1359 21 nt Target: 5′-CAUAAGGCUGUGCUGACCAUC-3′ (SEQ ID NO: 924)AAT-1360 21 nt Target: 5′-AUAAGGCUGUGCUGACCAUCG-3′ (SEQ ID NO: 925)AAT-1361 21 nt Target: 5′-UAAGGCUGUGCUGACCAUCGA-3′ (SEQ ID NO: 926)AAT-1390 21 nt Target: 5′-GGACUGAAGCUGCUGGGGCCA-3′ (SEQ ID NO: 927)AAT-1391 21 nt Target: 5′-GACUGAAGCUGCUGGGGCCAU-3′ (SEQ ID NO: 928)AAT-1392 21 nt Target: 5′-ACUGAAGCUGCUGGGGCCAUG-3′ (SEQ ID NO: 929)AAT-1393 21 nt Target: 5′-CUGAAGCUGCUGGGGCCAUGU-3′ (SEQ ID NO: 930)AAT-1394 21 nt Target: 5′-UGAAGCUGCUGGGGCCAUGUU-3′ (SEQ ID NO: 931)AAT-1395 21 nt Target: 5′-GAAGCUGCUGGGGCCAUGUUU-3′ (SEQ ID NO: 932)AAT-1405 21 nt Target: 5′-GGGCCAUGUUUUUAGAGGCCA-3′ (SEQ ID NO: 933)AAT-1406 21 nt Target: 5′-GGCCAUGUUUUUAGAGGCCAU-3′ (SEQ ID NO: 934)AAT-1407 21 nt Target: 5′-GCCAUGUUUUUAGAGGCCAUA-3′ (SEQ ID NO: 935)AAT-1408 21 nt Target: 5′-CCAUGUUUUUAGAGGCCAUAC-3′ (SEQ ID NO: 936)AAT-1409 21 nt Target: 5′-CAUGUUUUUAGAGGCCAUACC-3′ (SEQ ID NO: 937)AAT-1410 21 nt Target: 5′-AUGUUUUUAGAGGCCAUACCC-3′ (SEQ ID NO: 938)AAT-1411 21 nt Target: 5′-UGUUUUUAGAGGCCAUACCCA-3′ (SEQ ID NO: 939)AAT-1412 21 nt Target: 5′-GUUUUUAGAGGCCAUACCCAU-3′ (SEQ ID NO: 940)AAT-1413 21 nt Target: 5′-UUUUUAGAGGCCAUACCCAUG-3′ (SEQ ID NO: 941)AAT-1414 21 nt Target: 5′-UUUUAGAGGCCAUACCCAUGU-3′ (SEQ ID NO: 942)AAT-1415 21 nt Target: 5′-UUUAGAGGCCAUACCCAUGUC-3′ (SEQ ID NO: 943)AAT-1416 21 nt Target: 5′-UUAGAGGCCAUACCCAUGUCU-3′ (SEQ ID NO: 944)AAT-1452 21 nt Target: 5′-AAGUUCAACAAACCCUUUGUC-3′ (SEQ ID NO: 945)AAT-1453 21 nt Target: 5′-AGUUCAACAAACCCUUUGUCU-3′ (SEQ ID NO: 946)AAT-1454 21 nt Target: 5′-GUUCAACAAACCCUUUGUCUU-3′ (SEQ ID NO: 947)AAT-1455 21 nt Target: 5′-UUCAACAAACCCUUUGUCUUC-3′ (SEQ ID NO: 948)AAT-1456 21 nt Target: 5′-UCAACAAACCCUUUGUCUUCU-3′ (SEQ ID NO: 949)AAT-1457 21 nt Target: 5′-CAACAAACCCUUUGUCUUCUU-3′ (SEQ ID NO: 950)AAT-1458 21 nt Target: 5′-AACAAACCCUUUGUCUUCUUA-3′ (SEQ ID NO: 951)AAT-1459 21 nt Target: 5′-ACAAACCCUUUGUCUUCUUAA-3′ (SEQ ID NO: 952)AAT-1460 21 nt Target: 5′-CAAACCCUUUGUCUUCUUAAU-3′ (SEQ ID NO: 953)AAT-1489 21 nt Target: 5′-AAAAUACCAAGUCUCCCCUCU-3′ (SEQ ID NO: 954)AAT-1490 21 nt Target: 5′-AAAUACCAAGUCUCCCCUCUU-3′ (SEQ ID NO: 955)AAT-1491 21 nt Target: 5′-AAUACCAAGUCUCCCCUCUUC-3′ (SEQ ID NO: 956)AAT-1492 21 nt Target: 5′-AUACCAAGUCUCCCCUCUUCA-3′ (SEQ ID NO: 957)AAT-1493 21 nt Target: 5′-UACCAAGUCUCCCCUCUUCAU-3′ (SEQ ID NO: 958)AAT-1494 21 nt Target: 5′-ACCAAGUCUCCCCUCUUCAUG-3′ (SEQ ID NO: 959)AAT-1495 21 nt Target: 5′-CCAAGUCUCCCCUCUUCAUGG-3′ (SEQ ID NO: 960)AAT-1496 21 nt Target: 5′-CAAGUCUCCCCUCUUCAUGGG-3′ (SEQ ID NO: 961)AAT-1497 21 nt Target: 5′-AAGUCUCCCCUCUUCAUGGGA-3′ (SEQ ID NO: 962)AAT-1499 21 nt Target: 5′-GUCUCCCCUCUUCAUGGGAAA-3′ (SEQ ID NO: 963)AAT-1501 21 nt Target: 5′-CUCCCCUCUUCAUGGGAAAAG-3′ (SEQ ID NO: 964)AAT-1502 21 nt Target: 5′-UCCCCUCUUCAUGGGAAAAGU-3′ (SEQ ID NO: 965)AAT-1503 21 nt Target: 5′-CCCCUCUUCAUGGGAAAAGUG-3′ (SEQ ID NO: 966)AAT-1504 21 nt Target: 5′-CCCUCUUCAUGGGAAAAGUGG-3′ (SEQ ID NO: 967)AAT-1505 21 nt Target: 5′-CCUCUUCAUGGGAAAAGUGGU-3′ (SEQ ID NO: 968)AAT-1506 21 nt Target: 5′-CUCUUCAUGGGAAAAGUGGUG-3′ (SEQ ID NO: 969)AAT-1507 21 nt Target: 5′-UCUUCAUGGGAAAAGUGGUGA-3′ (SEQ ID NO: 970)AAT-1508 21 nt Target: 5′-CUUCAUGGGAAAAGUGGUGAA-3′ (SEQ ID NO: 971)AAT-1509 21 nt Target: 5′-UUCAUGGGAAAAGUGGUGAAU-3′ (SEQ ID NO: 972)AAT-1510 21 nt Target: 5′-UCAUGGGAAAAGUGGUGAAUC-3′ (SEQ ID NO: 973)AAT-1511 21 nt Target: 5′-CAUGGGAAAAGUGGUGAAUCC-3′ (SEQ ID NO: 974)AAT-1512 21 nt Target: 5′-AUGGGAAAAGUGGUGAAUCCC-3′ (SEQ ID NO: 975)AAT-1513 21 nt Target: 5′-UGGGAAAAGUGGUGAAUCCCA-3′ (SEQ ID NO: 976)AAT-1514 21 nt Target: 5′-GGGAAAAGUGGUGAAUCCCAC-3′ (SEQ ID NO: 977)AAT-1515 21 nt Target: 5′-GGAAAAGUGGUGAAUCCCACC-3′ (SEQ ID NO: 978)AAT-1516 21 nt Target: 5′-GAAAAGUGGUGAAUCCCACCC-3′ (SEQ ID NO: 979)AAT-1517 21 nt Target: 5′-AAAAGUGGUGAAUCCCACCCA-3′ (SEQ ID NO: 980)AAT-2872 21 nt Target: 5′-UUCGAUAGUUCAAAAUGGUGA-3′ (SEQ ID NO: 981)AAT-2880 21 nt Target: 5′-UUCAAAAUGGUGAAAUUAGCA-3′ (SEQ ID NO: 982)AAT-3167 21 nt Target: 5′-AGUUGGUAUGAUGUUCAAGUU-3′ (SEQ ID NO: 983)AAT-3169 21 nt Target: 5′-UUGGUAUGAUGUUCAAGUUAG-3′ (SEQ ID NO: 984)AAT-3170 21 nt Target: 5′-UGGUAUGAUGUUCAAGUUAGA-3′ (SEQ ID NO: 985)AAT-3172 21 nt Target: 5′-GUAUGAUGUUCAAGUUAGAUA-3′ (SEQ ID NO: 986)AAT-3175 21 nt Target: 5′-UGAUGUUCAAGUUAGAUAACA-3′ (SEQ ID NO: 987)AAT-3180 21 nt Target: 5′-UUCAAGUUAGAUAACAAAAUG-3′ (SEQ ID NO: 988)AAT-3181 21 nt Target: 5′-UCAAGUUAGAUAACAAAAUGU-3′ (SEQ ID NO: 989)AAT-3182 21 nt Target: 5′-CAAGUUAGAUAACAAAAUGUU-3′ (SEQ ID NO: 990)

TABLE 5 Selected Human Anti-α-1 antitrypsin “Blunt/Blunt” DsiRNAs5′-UACAUCCCACCAUGAUCAGGAUCACCC-3′ (SEQ ID NO: 991)3′-AUGUAGGGUGGUACUAGUCCUAGUGGG-5′ (SEQ ID NO: 199)AAT-395 Target: 5′-TACATCCCACCATGATCAGGATCACCC-3′ (SEQ ID NO: 397)5′-GCCAGCUGGCACACCAGUCCAACAGCA-3′ (SEQ ID NO: 992)3′-CGGUCGACCGUGUGGUCAGGUUGUCGU-5′ (SEQ ID NO: 200)AAT-475 Target: 5′-GCCAGCTGGCACACCAGTCCAACAGCA-3′ (SEQ ID NO: 398)5′-CAGCUGGCACACCAGUCCAACAGCACC-3′ (SEQ ID NO: 993)3′-GUCGACCGUGUGGUCAGGUUGUCGUGG-5′ (SEQ ID NO: 201)AAT-477 Target: 5′-CAGCTGGCACACCAGTCCAACAGCACC-3′ (SEQ ID NO: 399)5′-CUGGCACACCAGUCCAACAGCACCAAU-3′ (SEQ ID NO: 994)3′-GACCGUGUGGUCAGGUUGUCGUGGUUA-5′ (SEQ ID NO: 202)AAT-480 Target: 5′-CTGGCACACCAGTCCAACAGCACCAAT-3′ (SEQ ID NO: 400)5′-UGGCACACCAGUCCAACAGCACCAAUA-3′ (SEQ ID NO: 995)3′-ACCGUGUGGUCAGGUUGUCGUGGUUAU-5′ (SEQ ID NO: 203)AAT-481 Target: 5′-TGGCACACCAGTCCAACAGCACCAATA-3′ (SEQ ID NO: 401)5′-GGCACACCAGUCCAACAGCACCAAUAU-3′ (SEQ ID NO: 996)3′-CCGUGUGGUCAGGUUGUCGUGGUUAUA-5′ (SEQ ID NO: 204)AAT-482 Target: 5′-GGCACACCAGTCCAACAGCACCAATAT-3′ (SEQ ID NO: 402)5′-GCACACCAGUCCAACAGCACCAAUAUC-3′ (SEQ ID NO: 997)3′-CGUGUGGUCAGGUUGUCGUGGUUAUAG-5′ (SEQ ID NO: 205)AAT-483 Target: 5′-GCACACCAGTCCAACAGCACCAATATC-3′ (SEQ ID NO: 403)5′-CACACCAGUCCAACAGCACCAAUAUCU-3′ (SEQ ID NO: 998)3′-GUGUGGUCAGGUUGUCGUGGUUAUAGA-5′ (SEQ ID NO: 206)AAT-484 Target: 5′-CACACCAGTCCAACAGCACCAATATCT-3′ (SEQ ID NO: 404)5′-CACCAAUAUCUUCUUCUCCCCAGUGAG-3′ (SEQ ID NO: 999)3′-GUGGUUAUAGAAGAAGAGGGGUCACUC-5′ (SEQ ID NO: 207)AAT-500 Target: 5′-CACCAATATCTTCTTCTCCCCAGTGAG-3′ (SEQ ID NO: 405)5′-ACCAAUAUCUUCUUCUCCCCAGUGAGC-3′ (SEQ ID NO: 1000)3′-UGGUUAUAGAAGAAGAGGGGUCACUCG-5′ (SEQ ID NO: 208)AAT-501 Target: 5′-ACCAATATCTTCTTCTCCCCAGTGAGC-3′ (SEQ ID NO: 406)5′-CCAAUAUCUUCUUCUCCCCAGUGAGCA-3′ (SEQ ID NO: 1001)3′-GGUUAUAGAAGAAGAGGGGUCACUCGU-5′ (SEQ ID NO: 209)AAT-502 Target: 5′-CCAATATCTTCTTCTCCCCAGTGAGCA-3′ (SEQ ID NO: 407)5′-CAAUAUCUUCUUCUCCCCAGUGAGCAU-3′ (SEQ ID NO: 1002)3′-GUUAUAGAAGAAGAGGGGUCACUCGUA-5′ (SEQ ID NO: 210)AAT-503 Target: 5′-CAATATCTTCTTCTCCCCAGTGAGCAT-3′ (SEQ ID NO: 408)5′-AAUAUCUUCUUCUCCCCAGUGAGCAUC-3′ (SEQ ID NO: 1003)3′-UUAUAGAAGAAGAGGGGUCACUCGUAG-5′ (SEQ ID NO: 211)AAT-504 Target: 5′-AATATCTTCTTCTCCCCAGTGAGCATC-3′ (SEQ ID NO: 409)5′-AUAUCUUCUUCUCCCCAGUGAGCAUCG-3′ (SEQ ID NO: 1004)3′-UAUAGAAGAAGAGGGGUCACUCGUAGC-5′ (SEQ ID NO: 212)AAT-505 Target: 5′-ATATCTTCTTCTCCCCAGTGAGCATCG-3′ (SEQ ID NO: 410)5′-UAUCUUCUUCUCCCCAGUGAGCAUCGC-3′ (SEQ ID NO: 1005)3′-AUAGAAGAAGAGGGGUCACUCGUAGCG-5′ (SEQ ID NO: 213)AAT-506 Target: 5′-TATCTTCTTCTCCCCAGTGAGCATCGC-3′ (SEQ ID NO: 411)5′-AUCUUCUUCUCCCCAGUGAGCAUCGCU-3′ (SEQ ID NO: 1006)3′-UAGAAGAAGAGGGGUCACUCGUAGCGA-5′ (SEQ ID NO: 214)AAT-507 Target: 5′-ATCTTCTTCTCCCCAGTGAGCATCGCT-3′ (SEQ ID NO: 412)5′-UCUUCUUCUCCCCAGUGAGCAUCGCUA-3′ (SEQ ID NO: 1007)3′-AGAAGAAGAGGGGUCACUCGUAGCGAU-5′ (SEQ ID NO: 215)AAT-508 Target: 5′-TCTTCTTCTCCCCAGTGAGCATCGCTA-3′ (SEQ ID NO: 413)5′-CUUCUUCUCCCCAGUGAGCAUCGCUAC-3′ (SEQ ID NO: 1008)3′-GAAGAAGAGGGGUCACUCGUAGCGAUG-5′ (SEQ ID NO: 216)AAT-509 Target: 5′-CTTCTTCTCCCCAGTGAGCATCGCTAC-3′ (SEQ ID NO: 414)5′-UUCUUCUCCCCAGUGAGCAUCGCUACA-3′ (SEQ ID NO: 1009)3′-AAGAAGAGGGGUCACUCGUAGCGAUGU-5′ (SEQ ID NO: 217)AAT-510 Target: 5′-TTCTTCTCCCCAGTGAGCATCGCTACA-3′ (SEQ ID NO: 415)5′-CUUCUCCCCAGUGAGCAUCGCUACAGC-3′ (SEQ ID NO: 1010)3′-GAAGAGGGGUCACUCGUAGCGAUGUCG-5′ (SEQ ID NO: 218)AAT-512 Target: 5′-CTTCTCCCCAGTGAGCATCGCTACAGC-3′ (SEQ ID NO: 416)5′-UUCUCCCCAGUGAGCAUCGCUACAGCC-3′ (SEQ ID NO: 1011)3′-AAGAGGGGUCACUCGUAGCGAUGUCGG-5′ (SEQ ID NO: 219)AAT-513 Target: 5′-TTCTCCCCAGTGAGCATCGCTACAGCC-3′ (SEQ ID NO: 417)5′-CUCCCCAGUGAGCAUCGCUACAGCCUU-3′ (SEQ ID NO: 1012)3′-GAGGGGUCACUCGUAGCGAUGUCGGAA-5′ (SEQ ID NO: 220)AAT-515 Target: 5′-CTCCCCAGTGAGCATCGCTACAGCCTT-3′ (SEQ ID NO: 418)5′-CUACAGCCUUUGCAAUGCUCUCCCUGG-3′ (SEQ ID NO: 1013)3′-GAUGUCGGAAACGUUACGAGAGGGACC-5′ (SEQ ID NO: 221)AAT-532 Target: 5′-CTACAGCCTTTGCAATGCTCTCCCTGG-3′ (SEQ ID NO: 419)5′-UUUGCAAUGCUCUCCCUGGGGACCAAG-3′ (SEQ ID NO: 1014)3′-AAACGUUACGAGAGGGACCCCUGGUUC-5′ (SEQ ID NO: 222)AAT-540 Target: 5′-TTTGCAATGCTCTCCCTGGGGACCAAG-3′ (SEQ ID NO: 420)5′-UGAAAUCCUGGAGGGCCUGAAUUUCAA-3′ (SEQ ID NO: 1015)3′-ACUUUAGGACCUCCCGGACUUAAAGUU-5′ (SEQ ID NO: 223)AAT-581 Target: 5′-TGAAATCCTGGAGGGCCTGAATTTCAA-3′ (SEQ ID NO: 421)5′-GAAAUCCUGGAGGGCCUGAAUUUCAAC-3′ (SEQ ID NO: 1016)3′-CUUUAGGACCUCCCGGACUUAAAGUUG-5′ (SEQ ID NO: 224)AAT-582 Target: 5′-GAAATCCTGGAGGGCCTGAATTTCAAC-3′ (SEQ ID NO: 422)5′-AAAUCCUGGAGGGCCUGAAUUUCAACC-3′ (SEQ ID NO: 1017)3′-UUUAGGACCUCCCGGACUUAAAGUUGG-5′ (SEQ ID NO: 225)AAT-583 Target: 5′-AAATCCTGGAGGGCCTGAATTTCAACC-3′ (SEQ ID NO: 423)5′-AUCCUGGAGGGCCUGAAUUUCAACCUC-3′ (SEQ ID NO: 1018)3′-UAGGACCUCCCGGACUUAAAGUUGGAG-5′ (SEQ ID NO: 226)AAT-585 Target: 5′-ATCCTGGAGGGCCTGAATTTCAACCTC-3′ (SEQ ID NO: 424)5′-UCCUGGAGGGCCUGAAUUUCAACCUCA-3′ (SEQ ID NO: 1019)3′-AGGACCUCCCGGACUUAAAGUUGGAGU-5′ (SEQ ID NO: 227)AAT-586 Target: 5′-TCCTGGAGGGCCTGAATTTCAACCTCA-3′ (SEQ ID NO: 425)5′-CCUGGAGGGCCUGAAUUUCAACCUCAC-3′ (SEQ ID NO: 1020)3′-GGACCUCCCGGACUUAAAGUUGGAGUG-5′ (SEQ ID NO: 228)AAT-587 Target: 5′-CCTGGAGGGCCTGAATTTCAACCTCAC-3′ (SEQ ID NO: 426)5′-UCCAUGAAGGCUUCCAGGAACUCCUCC-3′ (SEQ ID NO: 1021)3′-AGGUACUUCCGAAGGUCCUUGAGGAGG-5′ (SEQ ID NO: 229)AAT-634 Target: 5′-TCCATGAAGGCTTCCAGGAACTCCTCC-3′ (SEQ ID NO: 427)5′-AUGAAGGCUUCCAGGAACUCCUCCGUA-3′ (SEQ ID NO: 1022)3′-UACUUCCGAAGGUCCUUGAGGAGGCAU-5′ (SEQ ID NO: 230)AAT-637 Target: 5′-ATGAAGGCTTCCAGGAACTCCTCCGTA-3′ (SEQ ID NO: 428)5′-UGAAGGCUUCCAGGAACUCCUCCGUAC-3′ (SEQ ID NO: 1023)3′-ACUUCCGAAGGUCCUUGAGGAGGCAUG-5′ (SEQ ID NO: 231)AAT-638 Target: 5′-TGAAGGCTTCCAGGAACTCCTCCGTAC-3′ (SEQ ID NO: 429)5′-CCAGCCAGACAGCCAGCUCCAGCUGAC-3′ (SEQ ID NO: 1024)3′-GGUCGGUCUGUCGGUCGAGGUCGACUG-5′ (SEQ ID NO: 232)AAT-671 Target: 5′-CCAGCCAGACAGCCAGCTCCAGCTGAC-3′ (SEQ ID NO: 430)5′-AGCCAGACAGCCAGCUCCAGCUGACCA-3′ (SEQ ID NO: 1025)3′-UCGGUCUGUCGGUCGAGGUCGACUGGU-5′ (SEQ ID NO: 233)AAT-673 Target: 5′-AGCCAGACAGCCAGCTCCAGCTGACCA-3′ (SEQ ID NO: 431)5′-CCAGACAGCCAGCUCCAGCUGACCACC-3′ (SEQ ID NO: 1026)3′-GGUCUGUCGGUCGAGGUCGACUGGUGG-5′ (SEQ ID NO: 234)AAT-675 Target: 5′-CCAGACAGCCAGCTCCAGCTGACCACC-3′ (SEQ ID NO: 432)5′-CAGACAGCCAGCUCCAGCUGACCACCG-3′ (SEQ ID NO: 1027)3′-GUCUGUCGGUCGAGGUCGACUGGUGGC-5′ (SEQ ID NO: 235)AAT-676 Target: 5′-CAGACAGCCAGCTCCAGCTGACCACCG-3′ (SEQ ID NO: 433)5′-GCUAGUGGAUAAGUUUUUGGAGGAUGU-3′ (SEQ ID NO: 1028)3′-CGAUCACCUAUUCAAAAACCUCCUACA-5′ (SEQ ID NO: 236)AAT-734 Target: 5′-GCTAGTGGATAAGTTTTTGGAGGATGT-3′ (SEQ ID NO: 434)5′-CUAGUGGAUAAGUUUUUGGAGGAUGUU-3′ (SEQ ID NO: 1029)3′-GAUCACCUAUUCAAAAACCUCCUACAA-5′ (SEQ ID NO: 237)AAT-735 Target: 5′-CTAGTGGATAAGTTTTTGGAGGATGTT-3′ (SEQ ID NO: 435)5′-UAGUGGAUAAGUUUUUGGAGGAUGUUA-3′ (SEQ ID NO: 1030)3′-AUCACCUAUUCAAAAACCUCCUACAAU-5′ (SEQ ID NO: 238)AAT-736 Target: 5′-TAGTGGATAAGTTTTTGGAGGATGTTA-3′ (SEQ ID NO: 436)5′-AGUGGAUAAGUUUUUGGAGGAUGUUAA-3′ (SEQ ID NO: 1031)3′-UCACCUAUUCAAAAACCUCCUACAAUU-5′ (SEQ ID NO: 239)AAT-737 Target: 5′-AGTGGATAAGTTTTTGGAGGATGTTAA-3′ (SEQ ID NO: 437)5′-GUGGAUAAGUUUUUGGAGGAUGUUAAA-3′ (SEQ ID NO: 1032)3′-CACCUAUUCAAAAACCUCCUACAAUUU-5′ (SEQ ID NO: 240)AAT-738 Target: 5′-GTGGATAAGTTTTTGGAGGATGTTAAA-3′ (SEQ ID NO: 438)5′-UGGAUAAGUUUUUGGAGGAUGUUAAAA-3′ (SEQ ID NO: 1033)3′-ACCUAUUCAAAAACCUCCUACAAUUUU-5′ (SEQ ID NO: 241)AAT-739 Target: 5′-TGGATAAGTTTTTGGAGGATGTTAAAA-3′ (SEQ ID NO: 439)5′-GGAUAAGUUUUUGGAGGAUGUUAAAAA-3′ (SEQ ID NO: 1034)3′-CCUAUUCAAAAACCUCCUACAAUUUUU-5′ (SEQ ID NO: 242)AAT-740 Target: 5′-GGATAAGTTTTTGGAGGATGTTAAAAA-3′ (SEQ ID NO: 440)5′-GUUGUACCACUCAGAAGCCUUCACUGU-3′ (SEQ ID NO: 1035)3′-CAACAUGGUGAGUCUUCGGAAGUGACA-5′ (SEQ ID NO: 243)AAT-767 Target: 5′-GTTGTACCACTCAGAAGCCTTCACTGT-3′ (SEQ ID NO: 441)5′-UUGUACCACUCAGAAGCCUUCACUGUC-3′ (SEQ ID NO: 1036)3′-AACAUGGUGAGUCUUCGGAAGUGACAG-5′ (SEQ ID NO: 244)AAT-768 Target: 5′-TTGTACCACTCAGAAGCCTTCACTGTC-3′ (SEQ ID NO: 442)5′-GUACUCAAGGGAAAAUUGUGGAUUUGG-3′ (SEQ ID NO: 1037)3′-CAUGAGUUCCCUUUUAACACCUAAACC-5′ (SEQ ID NO: 245)AAT-850 Target: 5′-GTACTCAAGGGAAAATTGTGGATTTGG-3′ (SEQ ID NO: 443)5′-UACUCAAGGGAAAAUUGUGGAUUUGGU-3′ (SEQ ID NO: 1038)3′-AUGAGUUCCCUUUUAACACCUAAACCA-5′ (SEQ ID NO: 246)AAT-851 Target: 5′-TACTCAAGGGAAAATTGTGGATTTGGT-3′ (SEQ ID NO: 444)5′-ACUCAAGGGAAAAUUGUGGAUUUGGUC-3′ (SEQ ID NO: 1039)3′-UGAGUUCCCUUUUAACACCUAAACCAG-5′ (SEQ ID NO: 247)AAT-852 Target: 5′-ACTCAAGGGAAAATTGTGGATTTGGTC-3′ (SEQ ID NO: 445)5′-CUCAAGGGAAAAUUGUGGAUUUGGUCA-3′ (SEQ ID NO: 1040)3′-GAGUUCCCUUUUAACACCUAAACCAGU-5′ (SEQ ID NO: 248)AAT-853 Target: 5′-CTCAAGGGAAAATTGTGGATTTGGTCA-3′ (SEQ ID NO: 446)5′-UCAAGGGAAAAUUGUGGAUUUGGUCAA-3′ (SEQ ID NO: 1041)3′-AGUUCCCUUUUAACACCUAAACCAGUU-5′ (SEQ ID NO: 249)AAT-854 Target: 5′-TCAAGGGAAAATTGTGGATTTGGTCAA-3′ (SEQ ID NO: 447)5′-CAAGGGAAAAUUGUGGAUUUGGUCAAG-3′ (SEQ ID NO: 1042)3′-GUUCCCUUUUAACACCUAAACCAGUUC-5′ (SEQ ID NO: 250)AAT-855 Target: 5′-CAAGGGAAAATTGTGGATTTGGTCAAG-3′ (SEQ ID NO: 448)5′-AAGGGAAAAUUGUGGAUUUGGUCAAGG-3′ (SEQ ID NO: 1043)3′-UUCCCUUUUAACACCUAAACCAGUUCC-5′ (SEQ ID NO: 251)AAT-856 Target: 5′-AAGGGAAAATTGTGGATTTGGTCAAGG-3′ (SEQ ID NO: 449)5′-AGGGAAAAUUGUGGAUUUGGUCAAGGA-3′ (SEQ ID NO: 1044)3′-UCCCUUUUAACACCUAAACCAGUUCCU-5′ (SEQ ID NO: 252)AAT-857 Target: 5′-AGGGAAAATTGTGGATTTGGTCAAGGA-3′ (SEQ ID NO: 450)5′-GGGAAAAUUGUGGAUUUGGUCAAGGAG-3′ (SEQ ID NO: 1045)3′-CCCUUUUAACACCUAAACCAGUUCCUC-5′ (SEQ ID NO: 253)AAT-858 Target: 5′-GGGAAAATTGTGGATTTGGTCAAGGAG-3′ (SEQ ID NO: 451)5′-GGAAAAUUGUGGAUUUGGUCAAGGAGC-3′ (SEQ ID NO: 1046)3′-CCUUUUAACACCUAAACCAGUUCCUCG-5′ (SEQ ID NO: 254)AAT-859 Target: 5′-GGAAAATTGTGGATTTGGTCAAGGAGC-3′ (SEQ ID NO: 452)5′-GAAAAUUGUGGAUUUGGUCAAGGAGCU-3′ (SEQ ID NO: 1047)3′-CUUUUAACACCUAAACCAGUUCCUCGA-5′ (SEQ ID NO: 255)AAT-860 Target: 5′-GAAAATTGTGGATTTGGTCAAGGAGCT-3′ (SEQ ID NO: 453)5′-AAAAUUGUGGAUUUGGUCAAGGAGCUU-3′ (SEQ ID NO: 1048)3′-UUUUAACACCUAAACCAGUUCCUCGAA-5′ (SEQ ID NO: 256)AAT-861 Target: 5′-AAAATTGTGGATTTGGTCAAGGAGCTT-3′ (SEQ ID NO: 454)5′-AAAUUGUGGAUUUGGUCAAGGAGCUUG-3′ (SEQ ID NO: 1049)3′-UUUAACACCUAAACCAGUUCCUCGAAC-5′ (SEQ ID NO: 257)AAT-862 Target: 5′-AAATTGTGGATTTGGTCAAGGAGCTTG-3′ (SEQ ID NO: 455)5′-AAUUGUGGAUUUGGUCAAGGAGCUUGA-3′ (SEQ ID NO: 1050)3′-UUAACACCUAAACCAGUUCCUCGAACU-5′ (SEQ ID NO: 258)AAT-863 Target: 5′-AATTGTGGATTTGGTCAAGGAGCTTGA-3′ (SEQ ID NO: 456)5′-AUUGUGGAUUUGGUCAAGGAGCUUGAC-3′ (SEQ ID NO: 1051)3′-UAACACCUAAACCAGUUCCUCGAACUG-5′ (SEQ ID NO: 259)AAT-864 Target: 5′-ATTGTGGATTTGGTCAAGGAGCTTGAC-3′ (SEQ ID NO: 457)5′-UUGUGGAUUUGGUCAAGGAGCUUGACA-3′ (SEQ ID NO: 1052)3′-AACACCUAAACCAGUUCCUCGAACUGU-5′ (SEQ ID NO: 260)AAT-865 Target: 5′-TTGTGGATTTGGTCAAGGAGCTTGACA-3′ (SEQ ID NO: 458)5′-UGUGGAUUUGGUCAAGGAGCUUGACAG-3′ (SEQ ID NO: 1053)3′-ACACCUAAACCAGUUCCUCGAACUGUC-5′ (SEQ ID NO: 261)AAT-866 Target: 5′-TGTGGATTTGGTCAAGGAGCTTGACAG-3′ (SEQ ID NO: 459)5′-GUGGAUUUGGUCAAGGAGCUUGACAGA-3′ (SEQ ID NO: 1054)3′-CACCUAAACCAGUUCCUCGAACUGUCU-5′ (SEQ ID NO: 262)AAT-867 Target: 5′-GTGGATTTGGTCAAGGAGCTTGACAGA-3′ (SEQ ID NO: 460)5′-UGGAUUUGGUCAAGGAGCUUGACAGAG-3′ (SEQ ID NO: 1055)3′-ACCUAAACCAGUUCCUCGAACUGUCUC-5′ (SEQ ID NO: 263)AAT-868 Target: 5′-TGGATTTGGTCAAGGAGCTTGACAGAG-3′ (SEQ ID NO: 461)5′-GGAUUUGGUCAAGGAGCUUGACAGAGA-3′ (SEQ ID NO: 1056)3′-CCUAAACCAGUUCCUCGAACUGUCUCU-5′ (SEQ ID NO: 264)AAT-869 Target: 5′-GGATTTGGTCAAGGAGCTTGACAGAGA-3′ (SEQ ID NO: 462)5′-GAUUUGGUCAAGGAGCUUGACAGAGAC-3′ (SEQ ID NO: 1057)3′-CUAAACCAGUUCCUCGAACUGUCUCUG-5′ (SEQ ID NO: 265)AAT-870 Target: 5′-GATTTGGTCAAGGAGCTTGACAGAGAC-3′ (SEQ ID NO: 463)5′-AUUUGGUCAAGGAGCUUGACAGAGACA-3′ (SEQ ID NO: 1058)3′-UAAACCAGUUCCUCGAACUGUCUCUGU-5′ (SEQ ID NO: 266)AAT-871 Target: 5′-ATTTGGTCAAGGAGCTTGACAGAGACA-3′ (SEQ ID NO: 464)5′-UUUGGUCAAGGAGCUUGACAGAGACAC-3′ (SEQ ID NO: 1059)3′-AAACCAGUUCCUCGAACUGUCUCUGUG-5′ (SEQ ID NO: 267)AAT-872 Target: 5′-TTTGGTCAAGGAGCTTGACAGAGACAC-3′ (SEQ ID NO: 465)5′-CACAGUUUUUGCUCUGGUGAAUUACAU-3′ (SEQ ID NO: 1060)3′-GUGUCAAAAACGAGACCACUUAAUGUA-5′ (SEQ ID NO: 268)AAT-896 Target: 5′-CACAGTTTTTGCTCTGGTGAATTACAT-3′ (SEQ ID NO: 466)5′-ACAGUUUUUGCUCUGGUGAAUUACAUC-3′ (SEQ ID NO: 1061)3′-UGUCAAAAACGAGACCACUUAAUGUAG-5′ (SEQ ID NO: 269)AAT-897 Target: 5′-ACAGTTTTTGCTCTGGTGAATTACATC-3′ (SEQ ID NO: 467)5′-CAGUUUUUGCUCUGGUGAAUUACAUCU-3′ (SEQ ID NO: 1062)3′-GUCAAAAACGAGACCACUUAAUGUAGA-5′ (SEQ ID NO: 270)AAT-898 Target: 5′-CAGTTTTTGCTCTGGTGAATTACATCT-3′ (SEQ ID NO: 468)5′-AGUUUUUGCUCUGGUGAAUUACAUCUU-3′ (SEQ ID NO: 1063)3′-UCAAAAACGAGACCACUUAAUGUAGAA-5′ (SEQ ID NO: 271)AAT-899 Target: 5′-AGTTTTTGCTCTGGTGAATTACATCTT-3′ (SEQ ID NO: 469)5′-UUAAAGGCAAAUGGGAGAGACCCUUUG-3′ (SEQ ID NO: 1064)3′-AAUUUCCGUUUACCCUCUCUGGGAAAC-5′ (SEQ ID NO: 272)AAT-928 Target: 5′-TTAAAGGCAAATGGGAGAGACCCTTTG-3′ (SEQ ID NO: 470)5′-UAAAGGCAAAUGGGAGAGACCCUUUGA-3′ (SEQ ID NO: 1065)3′-AUUUCCGUUUACCCUCUCUGGGAAACU-5′ (SEQ ID NO: 273)AAT-929 Target: 5′-TAAAGGCAAATGGGAGAGACCCTTTGA-3′ (SEQ ID NO: 471)5′-AAAGGCAAAUGGGAGAGACCCUUUGAA-3′ (SEQ ID NO: 1066)3′-UUUCCGUUUACCCUCUCUGGGAAACUU-5′ (SEQ ID NO: 274)AAT-930 Target: 5′-AAAGGCAAATGGGAGAGACCCTTTGAA-3′ (SEQ ID NO: 472)5′-AAGGCAAAUGGGAGAGACCCUUUGAAG-3′ (SEQ ID NO: 1067)3′-UUCCGUUUACCCUCUCUGGGAAACUUC-5′ (SEQ ID NO: 275)AAT-931 Target: 5′-AAGGCAAATGGGAGAGACCCTTTGAAG-3′ (SEQ ID NO: 473)5′-CGAGGAAGAGGACUUCCACGUGGACCA-3′ (SEQ ID NO: 1068)3′-GCUCCUUCUCCUGAAGGUGCACCUGGU-5′ (SEQ ID NO: 276)AAT-968 Target: 5′-CGAGGAAGAGGACTTCCACGTGGACCA-3′ (SEQ ID NO: 474)5′-GAGGAAGAGGACUUCCACGUGGACCAG-3′ (SEQ ID NO: 1069)3′-CUCCUUCUCCUGAAGGUGCACCUGGUC-5′ (SEQ ID NO: 277)AAT-969 Target: 5′-GAGGAAGAGGACTTCCACGTGGACCAG-3′ (SEQ ID NO: 475)5′-AGGAAGAGGACUUCCACGUGGACCAGG-3′ (SEQ ID NO: 1070)3′-UCCUUCUCCUGAAGGUGCACCUGGUCC-5′ (SEQ ID NO: 278)AAT-970 Target: 5′-AGGAAGAGGACTTCCACGTGGACCAGG-3′ (SEQ ID NO: 476)5′-GGAAGAGGACUUCCACGUGGACCAGGU-3′ (SEQ ID NO: 1071)3′-CCUUCUCCUGAAGGUGCACCUGGUCCA-5′ (SEQ ID NO: 279)AAT-971 Target: 5′-GGAAGAGGACTTCCACGTGGACCAGGT-3′ (SEQ ID NO: 477)5′-AAGAGGACUUCCACGUGGACCAGGUGA-3′ (SEQ ID NO: 1072)3′-UUCUCCUGAAGGUGCACCUGGUCCACU-5′ (SEQ ID NO: 280)AAT-973 Target: 5′-AAGAGGACTTCCACGTGGACCAGGTGA-3′ (SEQ ID NO: 478)5′-AGAGGACUUCCACGUGGACCAGGUGAC-3′ (SEQ ID NO: 1073)3′-UCUCCUGAAGGUGCACCUGGUCCACUG-5′ (SEQ ID NO: 281)AAT-974 Target: 5′-AGAGGACTTCCACGTGGACCAGGTGAC-3′ (SEQ ID NO: 479)5′-AGGACUUCCACGUGGACCAGGUGACCA-3′ (SEQ ID NO: 1074)3′-UCCUGAAGGUGCACCUGGUCCACUGGU-5′ (SEQ ID NO: 282)AAT-976 Target: 5′-AGGACTTCCACGTGGACCAGGTGACCA-3′ (SEQ ID NO: 480)5′-GCGUUUAGGCAUGUUUAACAUCCAGCA-3′ (SEQ ID NO: 1075)3′-CGCAAAUCCGUACAAAUUGUAGGUCGU-5′ (SEQ ID NO: 283)AAT-1025 Target: 5′-GCGTTTAGGCATGTTTAACATCCAGCA-3′ (SEQ ID NO: 481)5′-CGUUUAGGCAUGUUUAACAUCCAGCAC-3′ (SEQ ID NO: 1076)3′-GCAAAUCCGUACAAAUUGUAGGUCGUG-5′ (SEQ ID NO: 284)AAT-1026 Target: 5′-CGTTTAGGCATGTTTAACATCCAGCAC-3′ (SEQ ID NO: 482)5′-AAGCUGUCCAGCUGGGUGCUGCUGAUG-3′ (SEQ ID NO: 1077)3′-UUCGACAGGUCGACCCACGACGACUAC-5′ (SEQ ID NO: 285)AAT-1059 Target: 5′-AAGCTGTCCAGCTGGGTGCTGCTGATG-3′ (SEQ ID NO: 483)5′-AGCUGUCCAGCUGGGUGCUGCUGAUGA-3′ (SEQ ID NO: 1078)3′-UCGACAGGUCGACCCACGACGACUACU-5′ (SEQ ID NO: 286)AAT-1060 Target: 5′-AGCTGTCCAGCTGGGTGCTGCTGATGA-3′ (SEQ ID NO: 484)5′-GGCAAUGCCACCGCCAUCUUCUUCCUG-3′ (SEQ ID NO: 1079)3′-CCGUUACGGUGGCGGUAGAAGAAGGAC-5′ (SEQ ID NO: 287)AAT-1095 Target: 5′-GGCAATGCCACCGCCATCTTCTTCCTG-3′ (SEQ ID NO: 485)5′-GCAAUGCCACCGCCAUCUUCUUCCUGC-3′ (SEQ ID NO: 1080)3′-CGUUACGGUGGCGGUAGAAGAAGGACG-5′ (SEQ ID NO: 288)AAT-1096 Target: 5′-GCAATGCCACCGCCATCTTCTTCCTGC-3′ (SEQ ID NO: 486)5′-UGCCACCGCCAUCUUCUUCCUGCCUGA-3′ (SEQ ID NO: 1081)3′-ACGGUGGCGGUAGAAGAAGGACGGACU-5′ (SEQ ID NO: 289)AAT-1100 Target: 5′-TGCCACCGCCATCTTCTTCCTGCCTGA-3′ (SEQ ID NO: 487)5′-GCCACCGCCAUCUUCUUCCUGCCUGAU-3′ (SEQ ID NO: 1082)3′-CGGUGGCGGUAGAAGAAGGACGGACUA-5′ (SEQ ID NO: 290)AAT-1101 Target: 5′-GCCACCGCCATCTTCTTCCTGCCTGAT-3′ (SEQ ID NO: 488)5′-CCACCGCCAUCUUCUUCCUGCCUGAUG-3′ (SEQ ID NO: 1083)3′-GGUGGCGGUAGAAGAAGGACGGACUAC-5′ (SEQ ID NO: 291)AAT-1102 Target: 5′-CCACCGCCATCTTCTTCCTGCCTGATG-3′ (SEQ ID NO: 489)5′-CACCGCCAUCUUCUUCCUGCCUGAUGA-3′ (SEQ ID NO: 1084)3′-GUGGCGGUAGAAGAAGGACGGACUACU-5′ (SEQ ID NO: 292)AAT-1103 Target: 5′-CACCGCCATCTTCTTCCTGCCTGATGA-3′ (SEQ ID NO: 490)5′-ACCGCCAUCUUCUUCCUGCCUGAUGAG-3′ (SEQ ID NO: 1085)3′-UGGCGGUAGAAGAAGGACGGACUACUC-5′ (SEQ ID NO: 293)AAT-1104 Target: 5′-ACCGCCATCTTCTTCCTGCCTGATGAG-3′ (SEQ ID NO: 491)5′-CCGCCAUCUUCUUCCUGCCUGAUGAGG-3′ (SEQ ID NO: 1086)3′-GGCGGUAGAAGAAGGACGGACUACUCC-5′ (SEQ ID NO: 294)AAT-1105 Target: 5′-CCGCCATCTTCTTCCTGCCTGATGAGG-3′ (SEQ ID NO: 492)5′-CCAUCUUCUUCCUGCCUGAUGAGGGGA-3′ (SEQ ID NO: 1087)3′-GGUAGAAGAAGGACGGACUACUCCCCU-5′ (SEQ ID NO: 295)AAT-1108 Target: 5′-CCATCTTCTTCCTGCCTGATGAGGGGA-3′ (SEQ ID NO: 493)5′-UUCUUCCUGCCUGAUGAGGGGAAACUA-3′ (SEQ ID NO: 1088)3′-AAGAAGGACGGACUACUCCCCUUUGAU-5′ (SEQ ID NO: 296)AAT-1113 Target: 5′-TTCTTCCTGCCTGATGAGGGGAAACTA-3′ (SEQ ID NO: 494)5′-UCUUCCUGCCUGAUGAGGGGAAACUAC-3′ (SEQ ID NO: 1089)3′-AGAAGGACGGACUACUCCCCUUUGAUG-5′ (SEQ ID NO: 297)AAT-1114 Target: 5′-TCTTCCTGCCTGATGAGGGGAAACTAC-3′ (SEQ ID NO: 495)5′-CUUCCUGCCUGAUGAGGGGAAACUACA-3′ (SEQ ID NO: 1090)3′-GAAGGACGGACUACUCCCCUUUGAUGU-5′ (SEQ ID NO: 298)AAT-1115 Target: 5′-CTTCCTGCCTGATGAGGGGAAACTACA-3′ (SEQ ID NO: 496)5′-UUCCUGCCUGAUGAGGGGAAACUACAG-3′ (SEQ ID NO: 1091)3′-AAGGACGGACUACUCCCCUUUGAUGUC-5′ (SEQ ID NO: 299)AAT-1116 Target: 5′-TTCCTGCCTGATGAGGGGAAACTACAG-3′ (SEQ ID NO: 497)5′-UCCUGCCUGAUGAGGGGAAACUACAGC-3′ (SEQ ID NO: 1092)3′-AGGACGGACUACUCCCCUUUGAUGUCG-5′ (SEQ ID NO: 300)AAT-1117 Target: 5′-TCCTGCCTGATGAGGGGAAACTACAGC-3′ (SEQ ID NO: 498)5′-CCUGCCUGAUGAGGGGAAACUACAGCA-3′ (SEQ ID NO: 1093)3′-GGACGGACUACUCCCCUUUGAUGUCGU-5′ (SEQ ID NO: 301)AAT-1118 Target: 5′-CCTGCCTGATGAGGGGAAACTACAGCA-3′ (SEQ ID NO: 499)5′-ACAGCACCUGGAAAAUGAACUCACCCA-3′ (SEQ ID NO: 1094)3′-UGUCGUGGACCUUUUACUUGAGUGGGU-5′ (SEQ ID NO: 302)AAT-1139 Target: 5′-ACAGCACCTGGAAAATGAACTCACCCA-3′ (SEQ ID NO: 500)5′-CAGCACCUGGAAAAUGAACUCACCCAC-3′ (SEQ ID NO: 1095)3′-GUCGUGGACCUUUUACUUGAGUGGGUG-5′ (SEQ ID NO: 303)AAT-1140 Target: 5′-CAGCACCTGGAAAATGAACTCACCCAC-3′ (SEQ ID NO: 501)5′-AGCACCUGGAAAAUGAACUCACCCACG-3′ (SEQ ID NO: 1096)3′-UCGUGGACCUUUUACUUGAGUGGGUGC-5′ (SEQ ID NO: 304)AAT-1141 Target: 5′-AGCACCTGGAAAATGAACTCACCCACG-3′ (SEQ ID NO: 502)5′-GCACCUGGAAAAUGAACUCACCCACGA-3′ (SEQ ID NO: 1097)3′-CGUGGACCUUUUACUUGAGUGGGUGCU-5′ (SEQ ID NO: 305)AAT-1142 Target: 5′-GCACCTGGAAAATGAACTCACCCACGA-3′ (SEQ ID NO: 503)5′-CACCUGGAAAAUGAACUCACCCACGAU-3′ (SEQ ID NO: 1098)3′-GUGGACCUUUUACUUGAGUGGGUGCUA-5′ (SEQ ID NO: 306)AAT-1143 Target: 5′-CACCTGGAAAATGAACTCACCCACGAT-3′ (SEQ ID NO: 504)5′-CGAUAUCAUCACCAAGUUCCUGGAAAA-3′ (SEQ ID NO: 1099)3′-GCUAUAGUAGUGGUUCAAGGACCUUUU-5′ (SEQ ID NO: 307)AAT-1166 Target: 5′-CGATATCATCACCAAGTTCCTGGAAAA-3′ (SEQ ID NO: 505)5′-GAUAUCAUCACCAAGUUCCUGGAAAAU-3′ (SEQ ID NO: 1100)3′-CUAUAGUAGUGGUUCAAGGACCUUUUA-5′ (SEQ ID NO: 308)AAT-1167 Target: 5′-GATATCATCACCAAGTTCCTGGAAAAT-3′ (SEQ ID NO: 506)5′-AUAUCAUCACCAAGUUCCUGGAAAAUG-3′ (SEQ ID NO: 1101)3′-UAUAGUAGUGGUUCAAGGACCUUUUAC-5′ (SEQ ID NO: 309)AAT-1168 Target: 5′-ATATCATCACCAAGTTCCTGGAAAATG-3′ (SEQ ID NO: 507)5′-UAUCAUCACCAAGUUCCUGGAAAAUGA-3′ (SEQ ID NO: 1102)3′-AUAGUAGUGGUUCAAGGACCUUUUACU-5′ (SEQ ID NO: 310)AAT-1169 Target: 5′-TATCATCACCAAGTTCCTGGAAAATGA-3′ (SEQ ID NO: 508)5′-AUCAUCACCAAGUUCCUGGAAAAUGAA-3′ (SEQ ID NO: 1103)3′-UAGUAGUGGUUCAAGGACCUUUUACUU-5′ (SEQ ID NO: 311)AAT-1170 Target: 5′-ATCATCACCAAGTTCCTGGAAAATGAA-3′ (SEQ ID NO: 509)5′-UCAUCACCAAGUUCCUGGAAAAUGAAG-3′ (SEQ ID NO: 1104)3′-AGUAGUGGUUCAAGGACCUUUUACUUC-5′ (SEQ ID NO: 312)AAT-1171 Target: 5′-TCATCACCAAGTTCCTGGAAAATGAAG-3′ (SEQ ID NO: 510)5′-CAUCACCAAGUUCCUGGAAAAUGAAGA-3′ (SEQ ID NO: 1105)3′-GUAGUGGUUCAAGGACCUUUUACUUCU-5′ (SEQ ID NO: 313)AAT-1172 Target: 5′-CATCACCAAGTTCCTGGAAAATGAAGA-3′ (SEQ ID NO: 511)5′-AUCACCAAGUUCCUGGAAAAUGAAGAC-3′ (SEQ ID NO: 1106)3′-UAGUGGUUCAAGGACCUUUUACUUCUG-5′ (SEQ ID NO: 314)AAT-1173 Target: 5′-ATCACCAAGTTCCTGGAAAATGAAGAC-3′ (SEQ ID NO: 512)5′-UCACCAAGUUCCUGGAAAAUGAAGACA-3′ (SEQ ID NO: 1107)3′-AGUGGUUCAAGGACCUUUUACUUCUGU-5′ (SEQ ID NO: 315)AAT-1174 Target: 5′-TCACCAAGTTCCTGGAAAATGAAGACA-3′ (SEQ ID NO: 513)5′-CACCAAGUUCCUGGAAAAUGAAGACAG-3′ (SEQ ID NO: 1108)3′-GUGGUUCAAGGACCUUUUACUUCUGUC-5′ (SEQ ID NO: 316)AAT-1175 Target: 5′-CACCAAGTTCCTGGAAAATGAAGACAG-3′ (SEQ ID NO: 514)5′-UAAGGUCUUCAGCAAUGGGGCUGACCU-3′ (SEQ ID NO: 1109)3′-AUUCCAGAAGUCGUUACCCCGACUGGA-5′ (SEQ ID NO: 317)AAT-1286 Target: 5′-TAAGGTCTTCAGCAATGGGGCTGACCT-3′ (SEQ ID NO: 515)5′-AGCAAUGGGGCUGACCUCUCCGGGGUC-3′ (SEQ ID NO: 1110)3′-UCGUUACCCCGACUGGAGAGGCCCCAG-5′ (SEQ ID NO: 318)AAT-1296 Target: 5′-AGCAATGGGGCTGACCTCTCCGGGGTC-3′ (SEQ ID NO: 516)5′-GCAAUGGGGCUGACCUCUCCGGGGUCA-3′ (SEQ ID NO: 1111)3′-CGUUACCCCGACUGGAGAGGCCCCAGU-5′ (SEQ ID NO: 319)AAT-1297 Target: 5′-GCAATGGGGCTGACCTCTCCGGGGTCA-3′ (SEQ ID NO: 517)5′-CAAUGGGGCUGACCUCUCCGGGGUCAC-3′ (SEQ ID NO: 1112)3′-GUUACCCCGACUGGAGAGGCCCCAGUG-5′ (SEQ ID NO: 320)AAT-1298 Target: 5′-CAATGGGGCTGACCTCTCCGGGGTCAC-3′ (SEQ ID NO: 518)5′-CAGAGGAGGCACCCCUGAAGCUCUCCA-3′ (SEQ ID NO: 1113)3′-GUCUCCUCCGUGGGGACUUCGAGAGGU-5′ (SEQ ID NO: 321)AAT-1324 Target: 5′-CAGAGGAGGCACCCCTGAAGCTCTCCA-3′ (SEQ ID NO: 519)5′-GAGGAGGCACCCCUGAAGCUCUCCAAG-3′ (SEQ ID NO: 1114)3′-CUCCUCCGUGGGGACUUCGAGAGGUUC-5′ (SEQ ID NO: 322)AAT-1326 Target: 5′-GAGGAGGCACCCCTGAAGCTCTCCAAG-3′ (SEQ ID NO: 520)5′-CCCUGAAGCUCUCCAAGGCCGUGCAUA-3′ (SEQ ID NO: 1115)3′-GGGACUUCGAGAGGUUCCGGCACGUAU-5′ (SEQ ID NO: 323)AAT-1336 Target: 5′-CCCTGAAGCTCTCCAAGGCCGTGCATA-3′ (SEQ ID NO: 521)5′-GCCGUGCAUAAGGCUGUGCUGACCAUC-3′ (SEQ ID NO: 1116)3′-CGGCACGUAUUCCGACACGACUGGUAG-5′ (SEQ ID NO: 324)AAT-1353 Target: 5′-GCCGTGCATAAGGCTGTGCTGACCATC-3′ (SEQ ID NO: 522)5′-CCGUGCAUAAGGCUGUGCUGACCAUCG-3′ (SEQ ID NO: 1117)3′-GGCACGUAUUCCGACACGACUGGUAGC-5′ (SEQ ID NO: 325)AAT-1354 Target: 5′-CCGTGCATAAGGCTGTGCTGACCATCG-3′ (SEQ ID NO: 523)5′-CGUGCAUAAGGCUGUGCUGACCAUCGA-3′ (SEQ ID NO: 1118)3′-GCACGUAUUCCGACACGACUGGUAGCU-5′ (SEQ ID NO: 326)AAT-1355 Target: 5′-CGTGCATAAGGCTGTGCTGACCATCGA-3′ (SEQ ID NO: 524)5′-GUGCAUAAGGCUGUGCUGACCAUCGAC-3′ (SEQ ID NO: 1119)3′-CACGUAUUCCGACACGACUGGUAGCUG-5′ (SEQ ID NO: 327)AAT-1356 Target: 5′-GTGCATAAGGCTGTGCTGACCATCGAC-3′ (SEQ ID NO: 525)5′-UGCAUAAGGCUGUGCUGACCAUCGACG-3′ (SEQ ID NO: 1120)3′-ACGUAUUCCGACACGACUGGUAGCUGC-5′ (SEQ ID NO: 328)AAT-1357 Target: 5′-TGCATAAGGCTGTGCTGACCATCGACG-3′ (SEQ ID NO: 526)5′-GCAUAAGGCUGUGCUGACCAUCGACGA-3′ (SEQ ID NO: 1121)3′-CGUAUUCCGACACGACUGGUAGCUGCU-5′ (SEQ ID NO: 329)AAT-1358 Target: 5′-GCATAAGGCTGTGCTGACCATCGACGA-3′ (SEQ ID NO: 527)5′-CAUAAGGCUGUGCUGACCAUCGACGAG-3′ (SEQ ID NO: 1122)3′-GUAUUCCGACACGACUGGUAGCUGCUC-5′ (SEQ ID NO: 330)AAT-1359 Target: 5′-CATAAGGCTGTGCTGACCATCGACGAG-3′ (SEQ ID NO: 528)5′-AUAAGGCUGUGCUGACCAUCGACGAGA-3′ (SEQ ID NO: 1123)3′-UAUUCCGACACGACUGGUAGCUGCUCU-5′ (SEQ ID NO: 331)AAT-1360 Target: 5′-ATAAGGCTGTGCTGACCATCGACGAGA-3′ (SEQ ID NO: 529)5′-UAAGGCUGUGCUGACCAUCGACGAGAA-3′ (SEQ ID NO: 1124)3′-AUUCCGACACGACUGGUAGCUGCUCUU-5′ (SEQ ID NO: 332)AAT-1361 Target: 5′-TAAGGCTGTGCTGACCATCGACGAGAA-3′ (SEQ ID NO: 530)5′-GGACUGAAGCUGCUGGGGCCAUGUUUU-3′ (SEQ ID NO: 1125)3′-CCUGACUUCGACGACCCCGGUACAAAA-5′ (SEQ ID NO: 333)AAT-1390 Target: 5′-GGACTGAAGCTGCTGGGGCCATGTTTT-3′ (SEQ ID NO: 531)5′-GACUGAAGCUGCUGGGGCCAUGUUUUU-3′ (SEQ ID NO: 1126)3′-CUGACUUCGACGACCCCGGUACAAAAA-5′ (SEQ ID NO: 334)AAT-1391 Target: 5′-GACTGAAGCTGCTGGGGCCATGTTTTT-3′ (SEQ ID NO: 532)5′-ACUGAAGCUGCUGGGGCCAUGUUUUUA-3′ (SEQ ID NO: 1127)3′-UGACUUCGACGACCCCGGUACAAAAAU-5′ (SEQ ID NO: 335)AAT-1392 Target: 5′-ACTGAAGCTGCTGGGGCCATGTTTTTA-3′ (SEQ ID NO: 533)5′-CUGAAGCUGCUGGGGCCAUGUUUUUAG-3′ (SEQ ID NO: 1128)3′-GACUUCGACGACCCCGGUACAAAAAUC-5′ (SEQ ID NO: 336)AAT-1393 Target: 5′-CTGAAGCTGCTGGGGCCATGTTTTTAG-3′ (SEQ ID NO: 534)5′-UGAAGCUGCUGGGGCCAUGUUUUUAGA-3′ (SEQ ID NO: 1129)3′-ACUUCGACGACCCCGGUACAAAAAUCU-5′ (SEQ ID NO: 337)AAT-1394 Target: 5′-TGAAGCTGCTGGGGCCATGTTTTTAGA-3′ (SEQ ID NO: 535)5′-GAAGCUGCUGGGGCCAUGUUUUUAGAG-3′ (SEQ ID NO: 1130)3′-CUUCGACGACCCCGGUACAAAAAUCUC-5′ (SEQ ID NO: 338)AAT-1395 Target: 5′-GAAGCTGCTGGGGCCATGTTTTTAGAG-3′ (SEQ ID NO: 536)5′-GGGCCAUGUUUUUAGAGGCCAUACCCA-3′ (SEQ ID NO: 1131)3′-CCCGGUACAAAAAUCUCCGGUAUGGGU-5′ (SEQ ID NO: 339)AAT-1405 Target: 5′-GGGCCATGTTTTTAGAGGCCATACCCA-3′ (SEQ ID NO: 537)5′-GGCCAUGUUUUUAGAGGCCAUACCCAU-3′ (SEQ ID NO: 1132)3′-CCGGUACAAAAAUCUCCGGUAUGGGUA-5′ (SEQ ID NO: 340)AAT-1406 Target: 5′-GGCCATGTTTTTAGAGGCCATACCCAT-3′ (SEQ ID NO: 538)5′-GCCAUGUUUUUAGAGGCCAUACCCAUG-3′ (SEQ ID NO: 1133)3′-CGGUACAAAAAUCUCCGGUAUGGGUAC-5′ (SEQ ID NO: 341)AAT-1407 Target: 5′-GCCATGTTTTTAGAGGCCATACCCATG-3′ (SEQ ID NO: 539)5′-CCAUGUUUUUAGAGGCCAUACCCAUGU-3′ (SEQ ID NO: 1134)3′-GGUACAAAAAUCUCCGGUAUGGGUACA-5′ (SEQ ID NO: 342)AAT-1408 Target: 5′-CCATGTTTTTAGAGGCCATACCCATGT-3′ (SEQ ID NO: 540)5′-CAUGUUUUUAGAGGCCAUACCCAUGUC-3′ (SEQ ID NO: 1135)3′-GUACAAAAAUCUCCGGUAUGGGUACAG-5′ (SEQ ID NO: 343)AAT-1409 Target: 5′-CATGTTTTTAGAGGCCATACCCATGTC-3′ (SEQ ID NO: 541)5′-AUGUUUUUAGAGGCCAUACCCAUGUCU-3′ (SEQ ID NO: 1136)3′-UACAAAAAUCUCCGGUAUGGGUACAGA-5′ (SEQ ID NO: 344)AAT-1410 Target: 5′-ATGTTTTTAGAGGCCATACCCATGTCT-3′ (SEQ ID NO: 542)5′-UGUUUUUAGAGGCCAUACCCAUGUCUA-3′ (SEQ ID NO: 1137)3′-ACAAAAAUCUCCGGUAUGGGUACAGAU-5′ (SEQ ID NO: 345)AAT-1411 Target: 5′-TGTTTTTAGAGGCCATACCCATGTCTA-3′ (SEQ ID NO: 543)5′-GUUUUUAGAGGCCAUACCCAUGUCUAU-3′ (SEQ ID NO: 1138)3′-CAAAAAUCUCCGGUAUGGGUACAGAUA-5′ (SEQ ID NO: 346)AAT-1412 Target: 5′-GTTTTTAGAGGCCATACCCATGTCTAT-3′ (SEQ ID NO: 544)5′-UUUUUAGAGGCCAUACCCAUGUCUAUC-3′ (SEQ ID NO: 1139)3′-AAAAAUCUCCGGUAUGGGUACAGAUAG-5′ (SEQ ID NO: 347)AAT-1413 Target: 5′-TTTTTAGAGGCCATACCCATGTCTATC-3′ (SEQ ID NO: 545)5′-UUUUAGAGGCCAUACCCAUGUCUAUCC-3′ (SEQ ID NO: 1140)3′-AAAAUCUCCGGUAUGGGUACAGAUAGG-5′ (SEQ ID NO: 348)AAT-1414 Target: 5′-TTTTAGAGGCCATACCCATGTCTATCC-3′ (SEQ ID NO: 546)5′-UUUAGAGGCCAUACCCAUGUCUAUCCC-3′ (SEQ ID NO: 1141)3′-AAAUCUCCGGUAUGGGUACAGAUAGGG-5′ (SEQ ID NO: 349)AAT-1415 Target: 5′-TTTAGAGGCCATACCCATGTCTATCCC-3′ (SEQ ID NO: 547)5′-UUAGAGGCCAUACCCAUGUCUAUCCCC-3′ (SEQ ID NO: 1142)3′-AAUCUCCGGUAUGGGUACAGAUAGGGG-5′ (SEQ ID NO: 350)AAT-1416 Target: 5′-TTAGAGGCCATACCCATGTCTATCCCC-3′ (SEQ ID NO: 548)5′-AAGUUCAACAAACCCUUUGUCUUCUUA-3′ (SEQ ID NO: 1143)3′-UUCAAGUUGUUUGGGAAACAGAAGAAU-5′ (SEQ ID NO: 351)AAT-1452 Target: 5′-AAGTTCAACAAACCCTTTGTCTTCTTA-3′ (SEQ ID NO: 549)5′-AGUUCAACAAACCCUUUGUCUUCUUAA-3′ (SEQ ID NO: 1144)3′-UCAAGUUGUUUGGGAAACAGAAGAAUU-5′ (SEQ ID NO: 352)AAT-1453 Target: 5′-AGTTCAACAAACCCTTTGTCTTCTTAA-3′ (SEQ ID NO: 550)5′-GUUCAACAAACCCUUUGUCUUCUUAAU-3′ (SEQ ID NO: 1145)3′-CAAGUUGUUUGGGAAACAGAAGAAUUA-5′ (SEQ ID NO: 353)AAT-1454 Target: 5′-GTTCAACAAACCCTTTGTCTTCTTAAT-3′ (SEQ ID NO: 551)5′-UUCAACAAACCCUUUGUCUUCUUAAUG-3′ (SEQ ID NO: 1146)3′-AAGUUGUUUGGGAAACAGAAGAAUUAC-5′ (SEQ ID NO: 354)AAT-1455 Target: 5′-TTCAACAAACCCTTTGTCTTCTTAATG-3′ (SEQ ID NO: 552)5′-UCAACAAACCCUUUGUCUUCUUAAUGA-3′ (SEQ ID NO: 1147)3′-AGUUGUUUGGGAAACAGAAGAAUUACU-5′ (SEQ ID NO: 355)AAT-1456 Target: 5′-TCAACAAACCCTTTGTCTTCTTAATGA-3′ (SEQ ID NO: 553)5′-CAACAAACCCUUUGUCUUCUUAAUGAU-3′ (SEQ ID NO: 1148)3′-GUUGUUUGGGAAACAGAAGAAUUACUA-5′ (SEQ ID NO: 356)AAT-1457 Target: 5′-CAACAAACCCTTTGTCTTCTTAATGAT-3′ (SEQ ID NO: 554)5′-AACAAACCCUUUGUCUUCUUAAUGAUU-3′ (SEQ ID NO: 1149)3′-UUGUUUGGGAAACAGAAGAAUUACUAA-5′ (SEQ ID NO: 357)AAT-1458 Target: 5′-AACAAACCCTTTGTCTTCTTAATGATT-3′ (SEQ ID NO: 555)5′-ACAAACCCUUUGUCUUCUUAAUGAUUG-3′ (SEQ ID NO: 1150)3′-UGUUUGGGAAACAGAAGAAUUACUAAC-5′ (SEQ ID NO: 358)AAT-1459 Target: 5′-ACAAACCCTTTGTCTTCTTAATGATTG-3′ (SEQ ID NO: 556)5′-CAAACCCUUUGUCUUCUUAAUGAUUGA-3′ (SEQ ID NO: 1151)3′-GUUUGGGAAACAGAAGAAUUACUAACU-5′ (SEQ ID NO: 359)AAT-1460 Target: 5′-CAAACCCTTTGTCTTCTTAATGATTGA-3′ (SEQ ID NO: 557)5′-AAAAUACCAAGUCUCCCCUCUUCAUGG-3′ (SEQ ID NO: 1152)3′-UUUUAUGGUUCAGAGGGGAGAAGUACC-5′ (SEQ ID NO: 360)AAT-1489 Target: 5′-AAAATACCAAGTCTCCCCTCTTCATGG-3′ (SEQ ID NO: 558)5′-AAAUACCAAGUCUCCCCUCUUCAUGGG-3′ (SEQ ID NO: 1153)3′-UUUAUGGUUCAGAGGGGAGAAGUACCC-5′ (SEQ ID NO: 361)AAT-1490 Target: 5′-AAATACCAAGTCTCCCCTCTTCATGGG-3′ (SEQ ID NO: 559)5′-AAUACCAAGUCUCCCCUCUUCAUGGGA-3′ (SEQ ID NO: 1154)3′-UUAUGGUUCAGAGGGGAGAAGUACCCU-5′ (SEQ ID NO: 362)AAT-1491 Target: 5′-AATACCAAGTCTCCCCTCTTCATGGGA-3′ (SEQ ID NO: 560)5′-AUACCAAGUCUCCCCUCUUCAUGGGAA-3′ (SEQ ID NO: 1155)3′-UAUGGUUCAGAGGGGAGAAGUACCCUU-5′ (SEQ ID NO: 363)AAT-1492 Target: 5′-ATACCAAGTCTCCCCTCTTCATGGGAA-3′ (SEQ ID NO: 561)5′-UACCAAGUCUCCCCUCUUCAUGGGAAA-3′ (SEQ ID NO: 1156)3′-AUGGUUCAGAGGGGAGAAGUACCCUUU-5′ (SEQ ID NO: 364)AAT-1493 Target: 5′-TACCAAGTCTCCCCTCTTCATGGGAAA-3′ (SEQ ID NO: 562)5′-ACCAAGUCUCCCCUCUUCAUGGGAAAA-3′ (SEQ ID NO: 1157)3′-UGGUUCAGAGGGGAGAAGUACCCUUUU-5′ (SEQ ID NO: 365)AAT-1494 Target: 5′-ACCAAGTCTCCCCTCTTCATGGGAAAA-3′ (SEQ ID NO: 563)5′-CCAAGUCUCCCCUCUUCAUGGGAAAAG-3′ (SEQ ID NO: 1158)3′-GGUUCAGAGGGGAGAAGUACCCUUUUC-5′ (SEQ ID NO: 366)AAT-1495 Target: 5′-CCAAGTCTCCCCTCTTCATGGGAAAAG-3′ (SEQ ID NO: 564)5′-CAAGUCUCCCCUCUUCAUGGGAAAAGU-3′ (SEQ ID NO: 1159)3′-GUUCAGAGGGGAGAAGUACCCUUUUCA-5′ (SEQ ID NO: 367)AAT-1496 Target: 5′-CAAGTCTCCCCTCTTCATGGGAAAAGT-3′ (SEQ ID NO: 565)5′-AAGUCUCCCCUCUUCAUGGGAAAAGUG-3′ (SEQ ID NO: 1160)3′-UUCAGAGGGGAGAAGUACCCUUUUCAC-5′ (SEQ ID NO: 368)AAT-1497 Target: 5′-AAGTCTCCCCTCTTCATGGGAAAAGTG-3′ (SEQ ID NO: 566)5′-GUCUCCCCUCUUCAUGGGAAAAGUGGU-3′ (SEQ ID NO: 1161)3′-CAGAGGGGAGAAGUACCCUUUUCACCA-5′ (SEQ ID NO: 369)AAT-1499 Target: 5′-GTCTCCCCTCTTCATGGGAAAAGTGGT-3′ (SEQ ID NO: 567)5′-CUCCCCUCUUCAUGGGAAAAGUGGUGA-3′ (SEQ ID NO: 1162)3′-GAGGGGAGAAGUACCCUUUUCACCACU-5′ (SEQ ID NO: 370)AAT-1501 Target: 5′-CTCCCCTCTTCATGGGAAAAGTGGTGA-3′ (SEQ ID NO: 568)5′-UCCCCUCUUCAUGGGAAAAGUGGUGAA-3′ (SEQ ID NO: 1163)3′-AGGGGAGAAGUACCCUUUUCACCACUU-5′ (SEQ ID NO: 371)AAT-1502 Target: 5′-TCCCCTCTTCATGGGAAAAGTGGTGAA-3′ (SEQ ID NO: 569)5′-CCCCUCUUCAUGGGAAAAGUGGUGAAU-3′ (SEQ ID NO: 1164)3′-GGGGAGAAGUACCCUUUUCACCACUUA-5′ (SEQ ID NO: 372)AAT-1503 Target: 5′-CCCCTCTTCATGGGAAAAGTGGTGAAT-3′ (SEQ ID NO: 570)5′-CCCUCUUCAUGGGAAAAGUGGUGAAUC-3′ (SEQ ID NO: 1165)3′-GGGAGAAGUACCCUUUUCACCACUUAG-5′ (SEQ ID NO: 373)AAT-1504 Target: 5′-CCCTCTTCATGGGAAAAGTGGTGAATC-3′ (SEQ ID NO: 571)5′-CCUCUUCAUGGGAAAAGUGGUGAAUCC-3′ (SEQ ID NO: 1166)3′-GGAGAAGUACCCUUUUCACCACUUAGG-5′ (SEQ ID NO: 374)AAT-1505 Target: 5′-CCTCTTCATGGGAAAAGTGGTGAATCC-3′ (SEQ ID NO: 572)5′-CUCUUCAUGGGAAAAGUGGUGAAUCCC-3′ (SEQ ID NO: 1167)3′-GAGAAGUACCCUUUUCACCACUUAGGG-5′ (SEQ ID NO: 375)AAT-1506 Target: 5′-CTCTTCATGGGAAAAGTGGTGAATCCC-3′ (SEQ ID NO: 573)5′-UCUUCAUGGGAAAAGUGGUGAAUCCCA-3′ (SEQ ID NO: 1168)3′-AGAAGUACCCUUUUCACCACUUAGGGU-5′ (SEQ ID NO: 376)AAT-1507 Target: 5′-TCTTCATGGGAAAAGTGGTGAATCCCA-3′ (SEQ ID NO: 574)5′-CUUCAUGGGAAAAGUGGUGAAUCCCAC-3′ (SEQ ID NO: 1169)3′-GAAGUACCCUUUUCACCACUUAGGGUG-5′ (SEQ ID NO: 377)AAT-1508 Target: 5′-CTTCATGGGAAAAGTGGTGAATCCCAC-3′ (SEQ ID NO: 575)5′-UUCAUGGGAAAAGUGGUGAAUCCCACC-3′ (SEQ ID NO: 1170)3′-AAGUACCCUUUUCACCACUUAGGGUGG-5′ (SEQ ID NO: 378)AAT-1509 Target: 5′-TTCATGGGAAAAGTGGTGAATCCCACC-3′ (SEQ ID NO: 576)5′-UCAUGGGAAAAGUGGUGAAUCCCACCC-3′ (SEQ ID NO: 1171)3′-AGUACCCUUUUCACCACUUAGGGUGGG-5′ (SEQ ID NO: 379)AAT-1510 Target: 5′-TCATGGGAAAAGTGGTGAATCCCACCC-3′ (SEQ ID NO: 577)5′-CAUGGGAAAAGUGGUGAAUCCCACCCA-3′ (SEQ ID NO: 1172)3′-GUACCCUUUUCACCACUUAGGGUGGGU-5′ (SEQ ID NO: 380)AAT-1511 Target: 5′-CATGGGAAAAGTGGTGAATCCCACCCA-3′ (SEQ ID NO: 578)5′-AUGGGAAAAGUGGUGAAUCCCACCCAA-3′ (SEQ ID NO: 1173)3′-UACCCUUUUCACCACUUAGGGUGGGUU-5′ (SEQ ID NO: 381)AAT-1512 Target: 5′-ATGGGAAAAGTGGTGAATCCCACCCAA-3′ (SEQ ID NO: 579)5′-UGGGAAAAGUGGUGAAUCCCACCCAAA-3′ (SEQ ID NO: 1174)3′-ACCCUUUUCACCACUUAGGGUGGGUUU-5′ (SEQ ID NO: 382)AAT-1513 Target: 5′-TGGGAAAAGTGGTGAATCCCACCCAAA-3′ (SEQ ID NO: 580)5′-GGGAAAAGUGGUGAAUCCCACCCAAAA-3′ (SEQ ID NO: 1175)3′-CCCUUUUCACCACUUAGGGUGGGUUUU-5′ (SEQ ID NO: 383)AAT-1514 Target: 5′-GGGAAAAGTGGTGAATCCCACCCAAAA-3′ (SEQ ID NO: 581)5′-GGAAAAGUGGUGAAUCCCACCCAAAAA-3′ (SEQ ID NO: 1176)3′-CCUUUUCACCACUUAGGGUGGGUUUUU-5′ (SEQ ID NO: 384)AAT-1515 Target: 5′-GGAAAAGTGGTGAATCCCACCCAAAAA-3′ (SEQ ID NO: 582)5′-GAAAAGUGGUGAAUCCCACCCAAAAAU-3′ (SEQ ID NO: 1177)3′-CUUUUCACCACUUAGGGUGGGUUUUUA-5′ (SEQ ID NO: 385)AAT-1516 Target: 5′-GAAAAGTGGTGAATCCCACCCAAAAAT-3′ (SEQ ID NO: 583)5′-AAAAGUGGUGAAUCCCACCCAAAAAUA-3′ (SEQ ID NO: 1178)3′-UUUUCACCACUUAGGGUGGGUUUUUAU-5′ (SEQ ID NO: 386)AAT-1517 Target: 5′-AAAAGTGGTGAATCCCACCCAAAAATA-3′ (SEQ ID NO: 584)5′-UUCGAUAGUUCAAAAUGGUGAAAUUAG-3′ (SEQ ID NO: 1179)3′-AAGCUAUCAAGUUUUACCACUUUAAUC-5′ (SEQ ID NO: 387)AAT-2872 Target: 5′-TTCGATAGTTCAAAATGGTGAAATTAG-3′ (SEQ ID NO: 585)5′-UUCAAAAUGGUGAAAUUAGCAAUUCUA-3′ (SEQ ID NO: 1180)3′-AAGUUUUACCACUUUAAUCGUUAAGAU-5′ (SEQ ID NO: 388)AAT-2880 Target: 5′-TTCAAAATGGTGAAATTAGCAATTCTA-3′ (SEQ ID NO: 586)5′-AGUUGGUAUGAUGUUCAAGUUAGAUAA-3′ (SEQ ID NO: 1181)3′-UCAACCAUACUACAAGUUCAAUCUAUU-5′ (SEQ ID NO: 389)AAT-3167 Target: 5′-AGTTGGTATGATGTTCAAGTTAGATAA-3′ (SEQ ID NO: 587)5′-UUGGUAUGAUGUUCAAGUUAGAUAACA-3′ (SEQ ID NO: 1182)3′-AACCAUACUACAAGUUCAAUCUAUUGU-5′ (SEQ ID NO: 390)AAT-3169 Target: 5′-TTGGTATGATGTTCAAGTTAGATAACA-3′ (SEQ ID NO: 588)5′-UGGUAUGAUGUUCAAGUUAGAUAACAA-3′ (SEQ ID NO: 1183)3′-ACCAUACUACAAGUUCAAUCUAUUGUU-5′ (SEQ ID NO: 391)AAT-3170 Target: 5′-TGGTATGATGTTCAAGTTAGATAACAA-3′ (SEQ ID NO: 589)5′-GUAUGAUGUUCAAGUUAGAUAACAAAA-3′ (SEQ ID NO: 1184)3′-CAUACUACAAGUUCAAUCUAUUGUUUU-5′ (SEQ ID NO: 392)AAT-3172 Target: 5′-GTATGATGTTCAAGTTAGATAACAAAA-3′ (SEQ ID NO: 590)5′-UGAUGUUCAAGUUAGAUAACAAAAUGU-3′ (SEQ ID NO: 1185)3′-ACUACAAGUUCAAUCUAUUGUUUUACA-5′ (SEQ ID NO: 393)AAT-3175 Target: 5′-TGATGTTCAAGTTAGATAACAAAATGT-3′ (SEQ ID NO: 591)5′-UUCAAGUUAGAUAACAAAAUGUUUAUA-3′ (SEQ ID NO: 1186)3′-AAGUUCAAUCUAUUGUUUUACAAAUAU-5′ (SEQ ID NO: 394)AAT-3180 Target: 5′-TTCAAGTTAGATAACAAAATGTTTATA-3′ (SEQ ID NO: 592)5′-UCAAGUUAGAUAACAAAAUGUUUAUAC-3′ (SEQ ID NO: 1187)3′-AGUUCAAUCUAUUGUUUUACAAAUAUG-5′ (SEQ ID NO: 395)AAT-3181 Target: 5′-TCAAGTTAGATAACAAAATGTTTATAC-3′ (SEQ ID NO: 593)5′-CAAGUUAGAUAACAAAAUGUUUAUACC-3′ (SEQ ID NO: 1188)3′-GUUCAAUCUAUUGUUUUACAAAUAUGG-5′ (SEQ ID NO: 396)AAT-3182 Target: 5′-CAAGTTAGATAACAAAATGTTTATACC-3′ (SEQ ID NO: 594)

TABLE 6DsiRNA Component 19 Nucleotide Target Sequences in α-1 antitrypsin mRNAAAT-395 19 nt Target #1: 5′-CAUCCCACCAUGAUCAGGA-3′ (SEQ ID NO: 1189)AAT-395 19 nt Target #2: 5′-ACAUCCCACCAUGAUCAGG-3′ (SEQ ID NO: 1387)AAT-395 19 nt Target #3: 5′-UACAUCCCACCAUGAUCAG-3′ (SEQ ID NO: 1585)AAT-475 19 nt Target #1: 5′-CAGCUGGCACACCAGUCCA-3′ (SEQ ID NO: 1190)AAT-475 19 nt Target #2: 5′-CCAGCUGGCACACCAGUCC-3′ (SEQ ID NO: 1388)AAT-475 19 nt Target #3: 5′-GCCAGCUGGCACACCAGUC-3′ (SEQ ID NO: 1586)AAT-477 19 nt Target #1: 5′-GCUGGCACACCAGUCCAAC-3′ (SEQ ID NO: 1191)AAT-477 19 nt Target #2: 5′-AGCUGGCACACCAGUCCAA-3′ (SEQ ID NO: 1389)AAT-477 19 nt Target #3: 5′-CAGCUGGCACACCAGUCCA-3′ (SEQ ID NO: 1587)AAT-480 19 nt Target #1: 5′-GGCACACCAGUCCAACAGC-3′ (SEQ ID NO: 1192)AAT-480 19 nt Target #2: 5′-UGGCACACCAGUCCAACAG-3′ (SEQ ID NO: 1390)AAT-480 19 nt Target #3: 5′-CUGGCACACCAGUCCAACA-3′ (SEQ ID NO: 1588)AAT-481 19 nt Target #1: 5′-GCACACCAGUCCAACAGCA-3′ (SEQ ID NO: 1193)AAT-481 19 nt Target #2: 5′-GGCACACCAGUCCAACAGC-3′ (SEQ ID NO: 1391)AAT-481 19 nt Target #3: 5′-UGGCACACCAGUCCAACAG-3′ (SEQ ID NO: 1589)AAT-482 19 nt Target #1: 5′-CACACCAGUCCAACAGCAC-3′ (SEQ ID NO: 1194)AAT-482 19 nt Target #2: 5′-GCACACCAGUCCAACAGCA-3′ (SEQ ID NO: 1392)AAT-482 19 nt Target #3: 5′-GGCACACCAGUCCAACAGC-3′ (SEQ ID NO: 1590)AAT-483 19 nt Target #1: 5′-ACACCAGUCCAACAGCACC-3′ (SEQ ID NO: 1195)AAT-483 19 nt Target #2: 5′-CACACCAGUCCAACAGCAC-3′ (SEQ ID NO: 1393)AAT-483 19 nt Target #3: 5′-GCACACCAGUCCAACAGCA-3′ (SEQ ID NO: 1591)AAT-484 19 nt Target #1: 5′-CACCAGUCCAACAGCACCA-3′ (SEQ ID NO: 1196)AAT-484 19 nt Target #2: 5′-ACACCAGUCCAACAGCACC-3′ (SEQ ID NO: 1394)AAT-484 19 nt Target #3: 5′-CACACCAGUCCAACAGCAC-3′ (SEQ ID NO: 1592)AAT-500 19 nt Target #1: 5′-CCAAUAUCUUCUUCUCCCC-3′ (SEQ ID NO: 1197)AAT-500 19 nt Target #2: 5′-ACCAAUAUCUUCUUCUCCC-3′ (SEQ ID NO: 1395)AAT-500 19 nt Target #3: 5′-CACCAAUAUCUUCUUCUCC-3′ (SEQ ID NO: 1593)AAT-501 19 nt Target #1: 5′-CAAUAUCUUCUUCUCCCCA-3′ (SEQ ID NO: 1198)AAT-501 19 nt Target #2: 5′-CCAAUAUCUUCUUCUCCCC-3′ (SEQ ID NO: 1396)AAT-501 19 nt Target #3: 5′-ACCAAUAUCUUCUUCUCCC-3′ (SEQ ID NO: 1594)AAT-502 19 nt Target #1: 5′-AAUAUCUUCUUCUCCCCAG-3′ (SEQ ID NO: 1199)AAT-502 19 nt Target #2: 5′-CAAUAUCUUCUUCUCCCCA-3′ (SEQ ID NO: 1397)AAT-502 19 nt Target #3: 5′-CCAAUAUCUUCUUCUCCCC-3′ (SEQ ID NO: 1595)AAT-503 19 nt Target #1: 5′-AUAUCUUCUUCUCCCCAGU-3′ (SEQ ID NO: 1200)AAT-503 19 nt Target #2: 5′-AAUAUCUUCUUCUCCCCAG-3′ (SEQ ID NO: 1398)AAT-503 19 nt Target #3: 5′-CAAUAUCUUCUUCUCCCCA-3′ (SEQ ID NO: 1596)AAT-504 19 nt Target #1: 5′-UAUCUUCUUCUCCCCAGUG-3′ (SEQ ID NO: 1201)AAT-504 19 nt Target #2: 5′-AUAUCUUCUUCUCCCCAGU-3′ (SEQ ID NO: 1399)AAT-504 19 nt Target #3: 5′-AAUAUCUUCUUCUCCCCAG-3′ (SEQ ID NO: 1597)AAT-505 19 nt Target #1: 5′-AUCUUCUUCUCCCCAGUGA-3′ (SEQ ID NO: 1202)AAT-505 19 nt Target #2: 5′-UAUCUUCUUCUCCCCAGUG-3′ (SEQ ID NO: 1400)AAT-505 19 nt Target #3: 5′-AUAUCUUCUUCUCCCCAGU-3′ (SEQ ID NO: 1598)AAT-506 19 nt Target #1: 5′-UCUUCUUCUCCCCAGUGAG-3′ (SEQ ID NO: 1203)AAT-506 19 nt Target #2: 5′-AUCUUCUUCUCCCCAGUGA-3′ (SEQ ID NO: 1401)AAT-506 19 nt Target #3: 5′-UAUCUUCUUCUCCCCAGUG-3′ (SEQ ID NO: 1599)AAT-507 19 nt Target #1: 5′-CUUCUUCUCCCCAGUGAGC-3′ (SEQ ID NO: 1204)AAT-507 19 nt Target #2: 5′-UCUUCUUCUCCCCAGUGAG-3′ (SEQ ID NO: 1402)AAT-507 19 nt Target #3: 5′-AUCUUCUUCUCCCCAGUGA-3′ (SEQ ID NO: 1600)AAT-508 19 nt Target #1: 5′-UUCUUCUCCCCAGUGAGCA-3′ (SEQ ID NO: 1205)AAT-508 19 nt Target #2: 5′-CUUCUUCUCCCCAGUGAGC-3′ (SEQ ID NO: 1403)AAT-508 19 nt Target #3: 5′-UCUUCUUCUCCCCAGUGAG-3′ (SEQ ID NO: 1601)AAT-509 19 nt Target #1: 5′-UCUUCUCCCCAGUGAGCAU-3′ (SEQ ID NO: 1206)AAT-509 19 nt Target #2: 5′-UUCUUCUCCCCAGUGAGCA-3′ (SEQ ID NO: 1404)AAT-509 19 nt Target #3: 5′-CUUCUUCUCCCCAGUGAGC-3′ (SEQ ID NO: 1602)AAT-510 19 nt Target #1: 5′-CUUCUCCCCAGUGAGCAUC-3′ (SEQ ID NO: 1207)AAT-510 19 nt Target #2: 5′-UCUUCUCCCCAGUGAGCAU-3′ (SEQ ID NO: 1405)AAT-510 19 nt Target #3: 5′-UUCUUCUCCCCAGUGAGCA-3′ (SEQ ID NO: 1603)AAT-512 19 nt Target #1: 5′-UCUCCCCAGUGAGCAUCGC-3′ (SEQ ID NO: 1208)AAT-512 19 nt Target #2: 5′-UUCUCCCCAGUGAGCAUCG-3′ (SEQ ID NO: 1406)AAT-512 19 nt Target #3: 5′-CUUCUCCCCAGUGAGCAUC-3′ (SEQ ID NO: 1604)AAT-513 19 nt Target #1: 5′-CUCCCCAGUGAGCAUCGCU-3′ (SEQ ID NO: 1209)AAT-513 19 nt Target #2: 5′-UCUCCCCAGUGAGCAUCGC-3′ (SEQ ID NO: 1407)AAT-513 19 nt Target #3: 5′-UUCUCCCCAGUGAGCAUCG-3′ (SEQ ID NO: 1605)AAT-515 19 nt Target #1: 5′-CCCCAGUGAGCAUCGCUAC-3′ (SEQ ID NO: 1210)AAT-515 19 nt Target #2: 5′-UCCCCAGUGAGCAUCGCUA-3′ (SEQ ID NO: 1408)AAT-515 19 nt Target #3: 5′-CUCCCCAGUGAGCAUCGCU-3′ (SEQ ID NO: 1606)AAT-532 19 nt Target #1: 5′-ACAGCCUUUGCAAUGCUCU-3′ (SEQ ID NO: 1211)AAT-532 19 nt Target #2: 5′-UACAGCCUUUGCAAUGCUC-3′ (SEQ ID NO: 1409)AAT-532 19 nt Target #3: 5′-CUACAGCCUUUGCAAUGCU-3′ (SEQ ID NO: 1607)AAT-540 19 nt Target #1: 5′-UGCAAUGCUCUCCCUGGGG-3′ (SEQ ID NO: 1212)AAT-540 19 nt Target #2: 5′-UUGCAAUGCUCUCCCUGGG-3′ (SEQ ID NO: 1410)AAT-540 19 nt Target #3: 5′-UUUGCAAUGCUCUCCCUGG-3′ (SEQ ID NO: 1608)AAT-581 19 nt Target #1: 5′-AAAUCCUGGAGGGCCUGAA-3′ (SEQ ID NO: 1213)AAT-581 19 nt Target #2: 5′-GAAAUCCUGGAGGGCCUGA-3′ (SEQ ID NO: 1411)AAT-581 19 nt Target #3: 5′-UGAAAUCCUGGAGGGCCUG-3′ (SEQ ID NO: 1609)AAT-582 19 nt Target #1: 5′-AAUCCUGGAGGGCCUGAAU-3′ (SEQ ID NO: 1214)AAT-582 19 nt Target #2: 5′-AAAUCCUGGAGGGCCUGAA-3′ (SEQ ID NO: 1412)AAT-582 19 nt Target #3: 5′-GAAAUCCUGGAGGGCCUGA-3′ (SEQ ID NO: 1610)AAT-583 19 nt Target #1: 5′-AUCCUGGAGGGCCUGAAUU-3′ (SEQ ID NO: 1215)AAT-583 19 nt Target #2: 5′-AAUCCUGGAGGGCCUGAAU-3′ (SEQ ID NO: 1413)AAT-583 19 nt Target #3: 5′-AAAUCCUGGAGGGCCUGAA-3′ (SEQ ID NO: 1611)AAT-585 19 nt Target #1: 5′-CCUGGAGGGCCUGAAUUUC-3′ (SEQ ID NO: 1216)AAT-585 19 nt Target #2: 5′-UCCUGGAGGGCCUGAAUUU-3′ (SEQ ID NO: 1414)AAT-585 19 nt Target #3: 5′-AUCCUGGAGGGCCUGAAUU-3′ (SEQ ID NO: 1612)AAT-586 19 nt Target #1: 5′-CUGGAGGGCCUGAAUUUCA-3′ (SEQ ID NO: 1217)AAT-586 19 nt Target #2: 5′-CCUGGAGGGCCUGAAUUUC-3′ (SEQ ID NO: 1415)AAT-586 19 nt Target #3: 5′-UCCUGGAGGGCCUGAAUUU-3′ (SEQ ID NO: 1613)AAT-587 19 nt Target #1: 5′-UGGAGGGCCUGAAUUUCAA-3′ (SEQ ID NO: 1218)AAT-587 19 nt Target #2: 5′-CUGGAGGGCCUGAAUUUCA-3′ (SEQ ID NO: 1416)AAT-587 19 nt Target #3: 5′-CCUGGAGGGCCUGAAUUUC-3′ (SEQ ID NO: 1614)AAT-634 19 nt Target #1: 5′-CAUGAAGGCUUCCAGGAAC-3′ (SEQ ID NO: 1219)AAT-634 19 nt Target #2: 5′-CCAUGAAGGCUUCCAGGAA-3′ (SEQ ID NO: 1417)AAT-634 19 nt Target #3: 5′-UCCAUGAAGGCUUCCAGGA-3′ (SEQ ID NO: 1615)AAT-637 19 nt Target #1: 5′-GAAGGCUUCCAGGAACUCC-3′ (SEQ ID NO: 1220)AAT-637 19 nt Target #2: 5′-UGAAGGCUUCCAGGAACUC-3′ (SEQ ID NO: 1418)AAT-637 19 nt Target #3: 5′-AUGAAGGCUUCCAGGAACU-3′ (SEQ ID NO: 1616)AAT-638 19 nt Target #1: 5′-AAGGCUUCCAGGAACUCCU-3′ (SEQ ID NO: 1221)AAT-638 19 nt Target #2: 5′-GAAGGCUUCCAGGAACUCC-3′ (SEQ ID NO: 1419)AAT-638 19 nt Target #3: 5′-UGAAGGCUUCCAGGAACUC-3′ (SEQ ID NO: 1617)AAT-671 19 nt Target #1: 5′-AGCCAGACAGCCAGCUCCA-3′ (SEQ ID NO: 1222)AAT-671 19 nt Target #2: 5′-CAGCCAGACAGCCAGCUCC-3′ (SEQ ID NO: 1420)AAT-671 19 nt Target #3: 5′-CCAGCCAGACAGCCAGCUC-3′ (SEQ ID NO: 1618)AAT-673 19 nt Target #1: 5′-CCAGACAGCCAGCUCCAGC-3′ (SEQ ID NO: 1223)AAT-673 19 nt Target #2: 5′-GCCAGACAGCCAGCUCCAG-3′ (SEQ ID NO: 1421)AAT-673 19 nt Target #3: 5′-AGCCAGACAGCCAGCUCCA-3′ (SEQ ID NO: 1619)AAT-675 19 nt Target #1: 5′-AGACAGCCAGCUCCAGCUG-3′ (SEQ ID NO: 1224)AAT-675 19 nt Target #2: 5′-CAGACAGCCAGCUCCAGCU-3′ (SEQ ID NO: 1422)AAT-675 19 nt Target #3: 5′-CCAGACAGCCAGCUCCAGC-3′ (SEQ ID NO: 1620)AAT-676 19 nt Target #1: 5′-GACAGCCAGCUCCAGCUGA-3′ (SEQ ID NO: 1225)AAT-676 19 nt Target #2: 5′-AGACAGCCAGCUCCAGCUG-3′ (SEQ ID NO: 1423)AAT-676 19 nt Target #3: 5′-CAGACAGCCAGCUCCAGCU-3′ (SEQ ID NO: 1621)AAT-734 19 nt Target #1: 5′-UAGUGGAUAAGUUUUUGGA-3′ (SEQ ID NO: 1226)AAT-734 19 nt Target #2: 5′-CUAGUGGAUAAGUUUUUGG-3′ (SEQ ID NO: 1424)AAT-734 19 nt Target #3: 5′-GCUAGUGGAUAAGUUUUUG-3′ (SEQ ID NO: 1622)AAT-735 19 nt Target #1: 5′-AGUGGAUAAGUUUUUGGAG-3′ (SEQ ID NO: 1227)AAT-735 19 nt Target #2: 5′-UAGUGGAUAAGUUUUUGGA-3′ (SEQ ID NO: 1425)AAT-735 19 nt Target #3: 5′-CUAGUGGAUAAGUUUUUGG-3′ (SEQ ID NO: 1623)AAT-736 19 nt Target #1: 5′-GUGGAUAAGUUUUUGGAGG-3′ (SEQ ID NO: 1228)AAT-736 19 nt Target #2: 5′-AGUGGAUAAGUUUUUGGAG-3′ (SEQ ID NO: 1426)AAT-736 19 nt Target #3: 5′-UAGUGGAUAAGUUUUUGGA-3′ (SEQ ID NO: 1624)AAT-737 19 nt Target #1: 5′-UGGAUAAGUUUUUGGAGGA-3′ (SEQ ID NO: 1229)AAT-737 19 nt Target #2: 5′-GUGGAUAAGUUUUUGGAGG-3′ (SEQ ID NO: 1427)AAT-737 19 nt Target #3: 5′-AGUGGAUAAGUUUUUGGAG-3′ (SEQ ID NO: 1625)AAT-738 19 nt Target #1: 5′-GGAUAAGUUUUUGGAGGAU-3′ (SEQ ID NO: 1230)AAT-738 19 nt Target #2: 5′-UGGAUAAGUUUUUGGAGGA-3′ (SEQ ID NO: 1428)AAT-738 19 nt Target #3: 5′-GUGGAUAAGUUUUUGGAGG-3′ (SEQ ID NO: 1626)AAT-739 19 nt Target #1: 5′-GAUAAGUUUUUGGAGGAUG-3′ (SEQ ID NO: 1231)AAT-739 19 nt Target #2: 5′-GGAUAAGUUUUUGGAGGAU-3′ (SEQ ID NO: 1429)AAT-739 19 nt Target #3: 5′-UGGAUAAGUUUUUGGAGGA-3′ (SEQ ID NO: 1627)AAT-740 19 nt Target #1: 5′-AUAAGUUUUUGGAGGAUGU-3′ (SEQ ID NO: 1232)AAT-740 19 nt Target #2: 5′-GAUAAGUUUUUGGAGGAUG-3′ (SEQ ID NO: 1430)AAT-740 19 nt Target #3: 5′-GGAUAAGUUUUUGGAGGAU-3′ (SEQ ID NO: 1628)AAT-767 19 nt Target #1: 5′-UGUACCACUCAGAAGCCUU-3′ (SEQ ID NO: 1233)AAT-767 19 nt Target #2: 5′-UUGUACCACUCAGAAGCCU-3′ (SEQ ID NO: 1431)AAT-767 19 nt Target #3: 5′-GUUGUACCACUCAGAAGCC-3′ (SEQ ID NO: 1629)AAT-768 19 nt Target #1: 5′-GUACCACUCAGAAGCCUUC-3′ (SEQ ID NO: 1234)AAT-768 19 nt Target #2: 5′-UGUACCACUCAGAAGCCUU-3′ (SEQ ID NO: 1432)AAT-768 19 nt Target #3: 5′-UUGUACCACUCAGAAGCCU-3′ (SEQ ID NO: 1630)AAT-850 19 nt Target #1: 5′-ACUCAAGGGAAAAUUGUGG-3′ (SEQ ID NO: 1235)AAT-850 19 nt Target #2: 5′-UACUCAAGGGAAAAUUGUG-3′ (SEQ ID NO: 1433)AAT-850 19 nt Target #3: 5′-GUACUCAAGGGAAAAUUGU-3′ (SEQ ID NO: 1631)AAT-851 19 nt Target #1: 5′-CUCAAGGGAAAAUUGUGGA-3′ (SEQ ID NO: 1236)AAT-851 19 nt Target #2: 5′-ACUCAAGGGAAAAUUGUGG-3′ (SEQ ID NO: 1434)AAT-851 19 nt Target #3: 5′-UACUCAAGGGAAAAUUGUG-3′ (SEQ ID NO: 1632)AAT-852 19 nt Target #1: 5′-UCAAGGGAAAAUUGUGGAU-3′ (SEQ ID NO: 1237)AAT-852 19 nt Target #2: 5′-CUCAAGGGAAAAUUGUGGA-3′ (SEQ ID NO: 1435)AAT-852 19 nt Target #3: 5′-ACUCAAGGGAAAAUUGUGG-3′ (SEQ ID NO: 1633)AAT-853 19 nt Target #1: 5′-CAAGGGAAAAUUGUGGAUU-3′ (SEQ ID NO: 1238)AAT-853 19 nt Target #2: 5′-UCAAGGGAAAAUUGUGGAU-3′ (SEQ ID NO: 1436)AAT-853 19 nt Target #3: 5′-CUCAAGGGAAAAUUGUGGA-3′ (SEQ ID NO: 1634)AAT-854 19 nt Target #1: 5′-AAGGGAAAAUUGUGGAUUU-3′ (SEQ ID NO: 1239)AAT-854 19 nt Target #2: 5′-CAAGGGAAAAUUGUGGAUU-3′ (SEQ ID NO: 1437)AAT-854 19 nt Target #3: 5′-UCAAGGGAAAAUUGUGGAU-3′ (SEQ ID NO: 1635)AAT-855 19 nt Target #1: 5′-AGGGAAAAUUGUGGAUUUG-3′ (SEQ ID NO: 1240)AAT-855 19 nt Target #2: 5′-AAGGGAAAAUUGUGGAUUU-3′ (SEQ ID NO: 1438)AAT-855 19 nt Target #3: 5′-CAAGGGAAAAUUGUGGAUU-3′ (SEQ ID NO: 1636)AAT-856 19 nt Target #1: 5′-GGGAAAAUUGUGGAUUUGG-3′ (SEQ ID NO: 1241)AAT-856 19 nt Target #2: 5′-AGGGAAAAUUGUGGAUUUG-3′ (SEQ ID NO: 1439)AAT-856 19 nt Target #3: 5′-AAGGGAAAAUUGUGGAUUU-3′ (SEQ ID NO: 1637)AAT-857 19 nt Target #1: 5′-GGAAAAUUGUGGAUUUGGU-3′ (SEQ ID NO: 1242)AAT-857 19 nt Target #2: 5′-GGGAAAAUUGUGGAUUUGG-3′ (SEQ ID NO: 1440)AAT-857 19 nt Target #3: 5′-AGGGAAAAUUGUGGAUUUG-3′ (SEQ ID NO: 1638)AAT-858 19 nt Target #1: 5′-GAAAAUUGUGGAUUUGGUC-3′ (SEQ ID NO: 1243)AAT-858 19 nt Target #2: 5′-GGAAAAUUGUGGAUUUGGU-3′ (SEQ ID NO: 1441)AAT-858 19 nt Target #3: 5′-GGGAAAAUUGUGGAUUUGG-3′ (SEQ ID NO: 1639)AAT-859 19 nt Target #1: 5′-AAAAUUGUGGAUUUGGUCA-3′ (SEQ ID NO: 1244)AAT-859 19 nt Target #2: 5′-GAAAAUUGUGGAUUUGGUC-3′ (SEQ ID NO: 1442)AAT-859 19 nt Target #3: 5′-GGAAAAUUGUGGAUUUGGU-3′ (SEQ ID NO: 1640)AAT-860 19 nt Target #1: 5′-AAAUUGUGGAUUUGGUCAA-3′ (SEQ ID NO: 1245)AAT-860 19 nt Target #2: 5′-AAAAUUGUGGAUUUGGUCA-3′ (SEQ ID NO: 1443)AAT-860 19 nt Target #3: 5′-GAAAAUUGUGGAUUUGGUC-3′ (SEQ ID NO: 1641)AAT-861 19 nt Target #1: 5′-AAUUGUGGAUUUGGUCAAG-3′ (SEQ ID NO: 1246)AAT-861 19 nt Target #2: 5′-AAAUUGUGGAUUUGGUCAA-3′ (SEQ ID NO: 1444)AAT-861 19 nt Target #3: 5′-AAAAUUGUGGAUUUGGUCA-3′ (SEQ ID NO: 1642)AAT-862 19 nt Target #1: 5′-AUUGUGGAUUUGGUCAAGG-3′ (SEQ ID NO: 1247)AAT-862 19 nt Target #2: 5′-AAUUGUGGAUUUGGUCAAG-3′ (SEQ ID NO: 1445)AAT-862 19 nt Target #3: 5′-AAAUUGUGGAUUUGGUCAA-3′ (SEQ ID NO: 1643)AAT-863 19 nt Target #1: 5′-UUGUGGAUUUGGUCAAGGA-3′ (SEQ ID NO: 1248)AAT-863 19 nt Target #2: 5′-AUUGUGGAUUUGGUCAAGG-3′ (SEQ ID NO: 1446)AAT-863 19 nt Target #3: 5′-AAUUGUGGAUUUGGUCAAG-3′ (SEQ ID NO: 1644)AAT-864 19 nt Target #1: 5′-UGUGGAUUUGGUCAAGGAG-3′ (SEQ ID NO: 1249)AAT-864 19 nt Target #2: 5′-UUGUGGAUUUGGUCAAGGA-3′ (SEQ ID NO: 1447)AAT-864 19 nt Target #3: 5′-AUUGUGGAUUUGGUCAAGG-3′ (SEQ ID NO: 1645)AAT-865 19 nt Target #1: 5′-GUGGAUUUGGUCAAGGAGC-3′ (SEQ ID NO: 1250)AAT-865 19 nt Target #2: 5′-UGUGGAUUUGGUCAAGGAG-3′ (SEQ ID NO: 1448)AAT-865 19 nt Target #3: 5′-UUGUGGAUUUGGUCAAGGA-3′ (SEQ ID NO: 1646)AAT-866 19 nt Target #1: 5′-UGGAUUUGGUCAAGGAGCU-3′ (SEQ ID NO: 1251)AAT-866 19 nt Target #2: 5′-GUGGAUUUGGUCAAGGAGC-3′ (SEQ ID NO: 1449)AAT-866 19 nt Target #3: 5′-UGUGGAUUUGGUCAAGGAG-3′ (SEQ ID NO: 1647)AAT-867 19 nt Target #1: 5′-GGAUUUGGUCAAGGAGCUU-3′ (SEQ ID NO: 1252)AAT-867 19 nt Target #2: 5′-UGGAUUUGGUCAAGGAGCU-3′ (SEQ ID NO: 1450)AAT-867 19 nt Target #3: 5′-GUGGAUUUGGUCAAGGAGC-3′ (SEQ ID NO: 1648)AAT-868 19 nt Target #1: 5′-GAUUUGGUCAAGGAGCUUG-3′ (SEQ ID NO: 1253)AAT-868 19 nt Target #2: 5′-GGAUUUGGUCAAGGAGCUU-3′ (SEQ ID NO: 1451)AAT-868 19 nt Target #3: 5′-UGGAUUUGGUCAAGGAGCU-3′ (SEQ ID NO: 1649)AAT-869 19 nt Target #1: 5′-AUUUGGUCAAGGAGCUUGA-3′ (SEQ ID NO: 1254)AAT-869 19 nt Target #2: 5′-GAUUUGGUCAAGGAGCUUG-3′ (SEQ ID NO: 1452)AAT-869 19 nt Target #3: 5′-GGAUUUGGUCAAGGAGCUU-3′ (SEQ ID NO: 1650)AAT-870 19 nt Target #1: 5′-UUUGGUCAAGGAGCUUGAC-3′ (SEQ ID NO: 1255)AAT-870 19 nt Target #2: 5′-AUUUGGUCAAGGAGCUUGA-3′ (SEQ ID NO: 1453)AAT-870 19 nt Target #3: 5′-GAUUUGGUCAAGGAGCUUG-3′ (SEQ ID NO: 1651)AAT-871 19 nt Target #1: 5′-UUGGUCAAGGAGCUUGACA-3′ (SEQ ID NO: 1256)AAT-871 19 nt Target #2: 5′-UUUGGUCAAGGAGCUUGAC-3′ (SEQ ID NO: 1454)AAT-871 19 nt Target #3: 5′-AUUUGGUCAAGGAGCUUGA-3′ (SEQ ID NO: 1652)AAT-872 19 nt Target #1: 5′-UGGUCAAGGAGCUUGACAG-3′ (SEQ ID NO: 1257)AAT-872 19 nt Target #2: 5′-UUGGUCAAGGAGCUUGACA-3′ (SEQ ID NO: 1455)AAT-872 19 nt Target #3: 5′-UUUGGUCAAGGAGCUUGAC-3′ (SEQ ID NO: 1653)AAT-896 19 nt Target #1: 5′-CAGUUUUUGCUCUGGUGAA-3′ (SEQ ID NO: 1258)AAT-896 19 nt Target #2: 5′-ACAGUUUUUGCUCUGGUGA-3′ (SEQ ID NO: 1456)AAT-896 19 nt Target #3: 5′-CACAGUUUUUGCUCUGGUG-3′ (SEQ ID NO: 1654)AAT-897 19 nt Target #1: 5′-AGUUUUUGCUCUGGUGAAU-3′ (SEQ ID NO: 1259)AAT-897 19 nt Target #2: 5′-CAGUUUUUGCUCUGGUGAA-3′ (SEQ ID NO: 1457)AAT-897 19 nt Target #3: 5′-ACAGUUUUUGCUCUGGUGA-3′ (SEQ ID NO: 1655)AAT-898 19 nt Target #1: 5′-GUUUUUGCUCUGGUGAAUU-3′ (SEQ ID NO: 1260)AAT-898 19 nt Target #2: 5′-AGUUUUUGCUCUGGUGAAU-3′ (SEQ ID NO: 1458)AAT-898 19 nt Target #3: 5′-CAGUUUUUGCUCUGGUGAA-3′ (SEQ ID NO: 1656)AAT-899 19 nt Target #1: 5′-UUUUUGCUCUGGUGAAUUA-3′ (SEQ ID NO: 1261)AAT-899 19 nt Target #2: 5′-GUUUUUGCUCUGGUGAAUU-3′ (SEQ ID NO: 1459)AAT-899 19 nt Target #3: 5′-AGUUUUUGCUCUGGUGAAU-3′ (SEQ ID NO: 1657)AAT-928 19 nt Target #1: 5′-AAAGGCAAAUGGGAGAGAC-3′ (SEQ ID NO: 1262)AAT-928 19 nt Target #2: 5′-UAAAGGCAAAUGGGAGAGA-3′ (SEQ ID NO: 1460)AAT-928 19 nt Target #3: 5′-UUAAAGGCAAAUGGGAGAG-3′ (SEQ ID NO: 1658)AAT-929 19 nt Target #1: 5′-AAGGCAAAUGGGAGAGACC-3′ (SEQ ID NO: 1263)AAT-929 19 nt Target #2: 5′-AAAGGCAAAUGGGAGAGAC-3′ (SEQ ID NO: 1461)AAT-929 19 nt Target #3: 5′-UAAAGGCAAAUGGGAGAGA-3′ (SEQ ID NO: 1659)AAT-930 19 nt Target #1: 5′-AGGCAAAUGGGAGAGACCC-3′ (SEQ ID NO: 1264)AAT-930 19 nt Target #2: 5′-AAGGCAAAUGGGAGAGACC-3′ (SEQ ID NO: 1462)AAT-930 19 nt Target #3: 5′-AAAGGCAAAUGGGAGAGAC-3′ (SEQ ID NO: 1660)AAT-931 19 nt Target #1: 5′-GGCAAAUGGGAGAGACCCU-3′ (SEQ ID NO: 1265)AAT-931 19 nt Target #2: 5′-AGGCAAAUGGGAGAGACCC-3′ (SEQ ID NO: 1463)AAT-931 19 nt Target #3: 5′-AAGGCAAAUGGGAGAGACC-3′ (SEQ ID NO: 1661)AAT-968 19 nt Target #1: 5′-AGGAAGAGGACUUCCACGU-3′ (SEQ ID NO: 1266)AAT-968 19 nt Target #2: 5′-GAGGAAGAGGACUUCCACG-3′ (SEQ ID NO: 1464)AAT-968 19 nt Target #3: 5′-CGAGGAAGAGGACUUCCAC-3′ (SEQ ID NO: 1662)AAT-969 19 nt Target #1: 5′-GGAAGAGGACUUCCACGUG-3′ (SEQ ID NO: 1267)AAT-969 19 nt Target #2: 5′-AGGAAGAGGACUUCCACGU-3′ (SEQ ID NO: 1465)AAT-969 19 nt Target #3: 5′-GAGGAAGAGGACUUCCACG-3′ (SEQ ID NO: 1663)AAT-970 19 nt Target #1: 5′-GAAGAGGACUUCCACGUGG-3′ (SEQ ID NO: 1268)AAT-970 19 nt Target #2: 5′-GGAAGAGGACUUCCACGUG-3′ (SEQ ID NO: 1466)AAT-970 19 nt Target #3: 5′-AGGAAGAGGACUUCCACGU-3′ (SEQ ID NO: 1664)AAT-971 19 nt Target #1: 5′-AAGAGGACUUCCACGUGGA-3′ (SEQ ID NO: 1269)AAT-971 19 nt Target #2: 5′-GAAGAGGACUUCCACGUGG-3′ (SEQ ID NO: 1467)AAT-971 19 nt Target #3: 5′-GGAAGAGGACUUCCACGUG-3′ (SEQ ID NO: 1665)AAT-973 19 nt Target #1: 5′-GAGGACUUCCACGUGGACC-3′ (SEQ ID NO: 1270)AAT-973 19 nt Target #2: 5′-AGAGGACUUCCACGUGGAC-3′ (SEQ ID NO: 1468)AAT-973 19 nt Target #3: 5′-AAGAGGACUUCCACGUGGA-3′ (SEQ ID NO: 1666)AAT-974 19 nt Target #1: 5′-AGGACUUCCACGUGGACCA-3′ (SEQ ID NO: 1271)AAT-974 19 nt Target #2: 5′-GAGGACUUCCACGUGGACC-3′ (SEQ ID NO: 1469)AAT-974 19 nt Target #3: 5′-AGAGGACUUCCACGUGGAC-3′ (SEQ ID NO: 1667)AAT-976 19 nt Target #1: 5′-GACUUCCACGUGGACCAGG-3′ (SEQ ID NO: 1272)AAT-976 19 nt Target #2: 5′-GGACUUCCACGUGGACCAG-3′ (SEQ ID NO: 1470)AAT-976 19 nt Target #3: 5′-AGGACUUCCACGUGGACCA-3′ (SEQ ID NO: 1668)AAT-1025 19 nt Target #1: 5′-GUUUAGGCAUGUUUAACAU-3′ (SEQ ID NO: 1273)AAT-1025 19 nt Target #2: 5′-CGUUUAGGCAUGUUUAACA-3′ (SEQ ID NO: 1471)AAT-1025 19 nt Target #3: 5′-GCGUUUAGGCAUGUUUAAC-3′ (SEQ ID NO: 1669)AAT-1026 19 nt Target #1: 5′-UUUAGGCAUGUUUAACAUC-3′ (SEQ ID NO: 1274)AAT-1026 19 nt Target #2: 5′-GUUUAGGCAUGUUUAACAU-3′ (SEQ ID NO: 1472)AAT-1026 19 nt Target #3: 5′-CGUUUAGGCAUGUUUAACA-3′ (SEQ ID NO: 1670)AAT-1059 19 nt Target #1: 5′-GCUGUCCAGCUGGGUGCUG-3′ (SEQ ID NO: 1275)AAT-1059 19 nt Target #2: 5′-AGCUGUCCAGCUGGGUGCU-3′ (SEQ ID NO: 1473)AAT-1059 19 nt Target #3: 5′-AAGCUGUCCAGCUGGGUGC-3′ (SEQ ID NO: 1671)AAT-1060 19 nt Target #1: 5′-CUGUCCAGCUGGGUGCUGC-3′ (SEQ ID NO: 1276)AAT-1060 19 nt Target #2: 5′-GCUGUCCAGCUGGGUGCUG-3′ (SEQ ID NO: 1474)AAT-1060 19 nt Target #3: 5′-AGCUGUCCAGCUGGGUGCU-3′ (SEQ ID NO: 1672)AAT-1095 19 nt Target #1: 5′-CAAUGCCACCGCCAUCUUC-3′ (SEQ ID NO: 1277)AAT-1095 19 nt Target #2: 5′-GCAAUGCCACCGCCAUCUU-3′ (SEQ ID NO: 1475)AAT-1095 19 nt Target #3: 5′-GGCAAUGCCACCGCCAUCU-3′ (SEQ ID NO: 1673)AAT-1096 19 nt Target #1: 5′-AAUGCCACCGCCAUCUUCU-3′ (SEQ ID NO: 1278)AAT-1096 19 nt Target #2: 5′-CAAUGCCACCGCCAUCUUC-3′ (SEQ ID NO: 1476)AAT-1096 19 nt Target #3: 5′-GCAAUGCCACCGCCAUCUU-3′ (SEQ ID NO: 1674)AAT-1100 19 nt Target #1: 5′-CCACCGCCAUCUUCUUCCU-3′ (SEQ ID NO: 1279)AAT-1100 19 nt Target #2: 5′-GCCACCGCCAUCUUCUUCC-3′ (SEQ ID NO: 1477)AAT-1100 19 nt Target #3: 5′-UGCCACCGCCAUCUUCUUC-3′ (SEQ ID NO: 1675)AAT-1101 19 nt Target #1: 5′-CACCGCCAUCUUCUUCCUG-3′ (SEQ ID NO: 1280)AAT-1101 19 nt Target #2: 5′-CCACCGCCAUCUUCUUCCU-3′ (SEQ ID NO: 1478)AAT-1101 19 nt Target #3: 5′-GCCACCGCCAUCUUCUUCC-3′ (SEQ ID NO: 1676)AAT-1102 19 nt Target #1: 5′-ACCGCCAUCUUCUUCCUGC-3′ (SEQ ID NO: 1281)AAT-1102 19 nt Target #2: 5′-CACCGCCAUCUUCUUCCUG-3′ (SEQ ID NO: 1479)AAT-1102 19 nt Target #3: 5′-CCACCGCCAUCUUCUUCCU-3′ (SEQ ID NO: 1677)AAT-1103 19 nt Target #1: 5′-CCGCCAUCUUCUUCCUGCC-3′ (SEQ ID NO: 1282)AAT-1103 19 nt Target #2: 5′-ACCGCCAUCUUCUUCCUGC-3′ (SEQ ID NO: 1480)AAT-1103 19 nt Target #3: 5′-CACCGCCAUCUUCUUCCUG-3′ (SEQ ID NO: 1678)AAT-1104 19 nt Target #1: 5′-CGCCAUCUUCUUCCUGCCU-3′ (SEQ ID NO: 1283)AAT-1104 19 nt Target #2: 5′-CCGCCAUCUUCUUCCUGCC-3′ (SEQ ID NO: 1481)AAT-1104 19 nt Target #3: 5′-ACCGCCAUCUUCUUCCUGC-3′ (SEQ ID NO: 1679)AAT-1105 19 nt Target #1: 5′-GCCAUCUUCUUCCUGCCUG-3′ (SEQ ID NO: 1284)AAT-1105 19 nt Target #2: 5′-CGCCAUCUUCUUCCUGCCU-3′ (SEQ ID NO: 1482)AAT-1105 19 nt Target #3: 5′-CCGCCAUCUUCUUCCUGCC-3′ (SEQ ID NO: 1680)AAT-1108 19 nt Target #1: 5′-AUCUUCUUCCUGCCUGAUG-3′ (SEQ ID NO: 1285)AAT-1108 19 nt Target #2: 5′-CAUCUUCUUCCUGCCUGAU-3′ (SEQ ID NO: 1483)AAT-1108 19 nt Target #3: 5′-CCAUCUUCUUCCUGCCUGA-3′ (SEQ ID NO: 1681)AAT-1113 19 nt Target #1: 5′-CUUCCUGCCUGAUGAGGGG-3′ (SEQ ID NO: 1286)AAT-1113 19 nt Target #2: 5′-UCUUCCUGCCUGAUGAGGG-3′ (SEQ ID NO: 1484)AAT-1113 19 nt Target #3: 5′-UUCUUCCUGCCUGAUGAGG-3′ (SEQ ID NO: 1682)AAT-1114 19 nt Target #1: 5′-UUCCUGCCUGAUGAGGGGA-3′ (SEQ ID NO: 1287)AAT-1114 19 nt Target #2: 5′-CUUCCUGCCUGAUGAGGGG-3′ (SEQ ID NO: 1485)AAT-1114 19 nt Target #3: 5′-UCUUCCUGCCUGAUGAGGG-3′ (SEQ ID NO: 1683)AAT-1115 19 nt Target #1: 5′-UCCUGCCUGAUGAGGGGAA-3′ (SEQ ID NO: 1288)AAT-1115 19 nt Target #2: 5′-UUCCUGCCUGAUGAGGGGA-3′ (SEQ ID NO: 1486)AAT-1115 19 nt Target #3: 5′-CUUCCUGCCUGAUGAGGGG-3′ (SEQ ID NO: 1684)AAT-1116 19 nt Target #1: 5′-CCUGCCUGAUGAGGGGAAA-3′ (SEQ ID NO: 1289)AAT-1116 19 nt Target #2: 5′-UCCUGCCUGAUGAGGGGAA-3′ (SEQ ID NO: 1487)AAT-1116 19 nt Target #3: 5′-UUCCUGCCUGAUGAGGGGA-3′ (SEQ ID NO: 1685)AAT-1117 19 nt Target #1: 5′-CUGCCUGAUGAGGGGAAAC-3′ (SEQ ID NO: 1290)AAT-1117 19 nt Target #2: 5′-CCUGCCUGAUGAGGGGAAA-3′ (SEQ ID NO: 1488)AAT-1117 19 nt Target #3: 5′-UCCUGCCUGAUGAGGGGAA-3′ (SEQ ID NO: 1686)AAT-1118 19 nt Target #1: 5′-UGCCUGAUGAGGGGAAACU-3′ (SEQ ID NO: 1291)AAT-1118 19 nt Target #2: 5′-CUGCCUGAUGAGGGGAAAC-3′ (SEQ ID NO: 1489)AAT-1118 19 nt Target #3: 5′-CCUGCCUGAUGAGGGGAAA-3′ (SEQ ID NO: 1687)AAT-1139 19 nt Target #1: 5′-AGCACCUGGAAAAUGAACU-3′ (SEQ ID NO: 1292)AAT-1139 19 nt Target #2: 5′-CAGCACCUGGAAAAUGAAC-3′ (SEQ ID NO: 1490)AAT-1139 19 nt Target #3: 5′-ACAGCACCUGGAAAAUGAA-3′ (SEQ ID NO: 1688)AAT-1140 19 nt Target #1: 5′-GCACCUGGAAAAUGAACUC-3′ (SEQ ID NO: 1293)AAT-1140 19 nt Target #2: 5′-AGCACCUGGAAAAUGAACU-3′ (SEQ ID NO: 1491)AAT-1140 19 nt Target #3: 5′-CAGCACCUGGAAAAUGAAC-3′ (SEQ ID NO: 1689)AAT-1141 19 nt Target #1: 5′-CACCUGGAAAAUGAACUCA-3′ (SEQ ID NO: 1294)AAT-1141 19 nt Target #2: 5′-GCACCUGGAAAAUGAACUC-3′ (SEQ ID NO: 1492)AAT-1141 19 nt Target #3: 5′-AGCACCUGGAAAAUGAACU-3′ (SEQ ID NO: 1690)AAT-1142 19 nt Target #1: 5′-ACCUGGAAAAUGAACUCAC-3′ (SEQ ID NO: 1295)AAT-1142 19 nt Target #2: 5′-CACCUGGAAAAUGAACUCA-3′ (SEQ ID NO: 1493)AAT-1142 19 nt Target #3: 5′-GCACCUGGAAAAUGAACUC-3′ (SEQ ID NO: 1691)AAT-1143 19 nt Target #1: 5′-CCUGGAAAAUGAACUCACC-3′ (SEQ ID NO: 1296)AAT-1143 19 nt Target #2: 5′-ACCUGGAAAAUGAACUCAC-3′ (SEQ ID NO: 1494)AAT-1143 19 nt Target #3: 5′-CACCUGGAAAAUGAACUCA-3′ (SEQ ID NO: 1692)AAT-1166 19 nt Target #1: 5′-AUAUCAUCACCAAGUUCCU-3′ (SEQ ID NO: 1297)AAT-1166 19 nt Target #2: 5′-GAUAUCAUCACCAAGUUCC-3′ (SEQ ID NO: 1495)AAT-1166 19 nt Target #3: 5′-CGAUAUCAUCACCAAGUUC-3′ (SEQ ID NO: 1693)AAT-1167 19 nt Target #1: 5′-UAUCAUCACCAAGUUCCUG-3′ (SEQ ID NO: 1298)AAT-1167 19 nt Target #2: 5′-AUAUCAUCACCAAGUUCCU-3′ (SEQ ID NO: 1496)AAT-1167 19 nt Target #3: 5′-GAUAUCAUCACCAAGUUCC-3′ (SEQ ID NO: 1694)AAT-1168 19 nt Target #1: 5′-AUCAUCACCAAGUUCCUGG-3′ (SEQ ID NO: 1299)AAT-1168 19 nt Target #2: 5′-UAUCAUCACCAAGUUCCUG-3′ (SEQ ID NO: 1497)AAT-1168 19 nt Target #3: 5′-AUAUCAUCACCAAGUUCCU-3′ (SEQ ID NO: 1695)AAT-1169 19 nt Target #1: 5′-UCAUCACCAAGUUCCUGGA-3′ (SEQ ID NO: 1300)AAT-1169 19 nt Target #2: 5′-AUCAUCACCAAGUUCCUGG-3′ (SEQ ID NO: 1498)AAT-1169 19 nt Target #3: 5′-UAUCAUCACCAAGUUCCUG-3′ (SEQ ID NO: 1696)AAT-1170 19 nt Target #1: 5′-CAUCACCAAGUUCCUGGAA-3′ (SEQ ID NO: 1301)AAT-1170 19 nt Target #2: 5′-UCAUCACCAAGUUCCUGGA-3′ (SEQ ID NO: 1499)AAT-1170 19 nt Target #3: 5′-AUCAUCACCAAGUUCCUGG-3′ (SEQ ID NO: 1697)AAT-1171 19 nt Target #1: 5′-AUCACCAAGUUCCUGGAAA-3′ (SEQ ID NO: 1302)AAT-1171 19 nt Target #2: 5′-CAUCACCAAGUUCCUGGAA-3′ (SEQ ID NO: 1500)AAT-1171 19 nt Target #3: 5′-UCAUCACCAAGUUCCUGGA-3′ (SEQ ID NO: 1698)AAT-1172 19 nt Target #1: 5′-UCACCAAGUUCCUGGAAAA-3′ (SEQ ID NO: 1303)AAT-1172 19 nt Target #2: 5′-AUCACCAAGUUCCUGGAAA-3′ (SEQ ID NO: 1501)AAT-1172 19 nt Target #3: 5′-CAUCACCAAGUUCCUGGAA-3′ (SEQ ID NO: 1699)AAT-1173 19 nt Target #1: 5′-CACCAAGUUCCUGGAAAAU-3′ (SEQ ID NO: 1304)AAT-1173 19 nt Target #2: 5′-UCACCAAGUUCCUGGAAAA-3′ (SEQ ID NO: 1502)AAT-1173 19 nt Target #3: 5′-AUCACCAAGUUCCUGGAAA-3′ (SEQ ID NO: 1700)AAT-1174 19 nt Target #1: 5′-ACCAAGUUCCUGGAAAAUG-3′ (SEQ ID NO: 1305)AAT-1174 19 nt Target #2: 5′-CACCAAGUUCCUGGAAAAU-3′ (SEQ ID NO: 1503)AAT-1174 19 nt Target #3: 5′-UCACCAAGUUCCUGGAAAA-3′ (SEQ ID NO: 1701)AAT-1175 19 nt Target #1: 5′-CCAAGUUCCUGGAAAAUGA-3′ (SEQ ID NO: 1306)AAT-1175 19 nt Target #2: 5′-ACCAAGUUCCUGGAAAAUG-3′ (SEQ ID NO: 1504)AAT-1175 19 nt Target #3: 5′-CACCAAGUUCCUGGAAAAU-3′ (SEQ ID NO: 1702)AAT-1286 19 nt Target #1: 5′-AGGUCUUCAGCAAUGGGGC-3′ (SEQ ID NO: 1307)AAT-1286 19 nt Target #2: 5′-AAGGUCUUCAGCAAUGGGG-3′ (SEQ ID NO: 1505)AAT-1286 19 nt Target #3: 5′-UAAGGUCUUCAGCAAUGGG-3′ (SEQ ID NO: 1703)AAT-1296 19 nt Target #1: 5′-CAAUGGGGCUGACCUCUCC-3′ (SEQ ID NO: 1308)AAT-1296 19 nt Target #2: 5′-GCAAUGGGGCUGACCUCUC-3′ (SEQ ID NO: 1506)AAT-1296 19 nt Target #3: 5′-AGCAAUGGGGCUGACCUCU-3′ (SEQ ID NO: 1704)AAT-1297 19 nt Target #1: 5′-AAUGGGGCUGACCUCUCCG-3′ (SEQ ID NO: 1309)AAT-1297 19 nt Target #2: 5′-CAAUGGGGCUGACCUCUCC-3′ (SEQ ID NO: 1507)AAT-1297 19 nt Target #3: 5′-GCAAUGGGGCUGACCUCUC-3′ (SEQ ID NO: 1705)AAT-1298 19 nt Target #1: 5′-AUGGGGCUGACCUCUCCGG-3′ (SEQ ID NO: 1310)AAT-1298 19 nt Target #2: 5′-AAUGGGGCUGACCUCUCCG-3′ (SEQ ID NO: 1508)AAT-1298 19 nt Target #3: 5′-CAAUGGGGCUGACCUCUCC-3′ (SEQ ID NO: 1706)AAT-1324 19 nt Target #1: 5′-GAGGAGGCACCCCUGAAGC-3′ (SEQ ID NO: 1311)AAT-1324 19 nt Target #2: 5′-AGAGGAGGCACCCCUGAAG-3′ (SEQ ID NO: 1509)AAT-1324 19 nt Target #3: 5′-CAGAGGAGGCACCCCUGAA-3′ (SEQ ID NO: 1707)AAT-1326 19 nt Target #1: 5′-GGAGGCACCCCUGAAGCUC-3′ (SEQ ID NO: 1312)AAT-1326 19 nt Target #2: 5′-AGGAGGCACCCCUGAAGCU-3′ (SEQ ID NO: 1510)AAT-1326 19 nt Target #3: 5′-GAGGAGGCACCCCUGAAGC-3′ (SEQ ID NO: 1708)AAT-1336 19 nt Target #1: 5′-CUGAAGCUCUCCAAGGCCG-3′ (SEQ ID NO: 1313)AAT-1336 19 nt Target #2: 5′-CCUGAAGCUCUCCAAGGCC-3′ (SEQ ID NO: 1511)AAT-1336 19 nt Target #3: 5′-CCCUGAAGCUCUCCAAGGC-3′ (SEQ ID NO: 1709)AAT-1353 19 nt Target #1: 5′-CGUGCAUAAGGCUGUGCUG-3′ (SEQ ID NO: 1314)AAT-1353 19 nt Target #2: 5′-CCGUGCAUAAGGCUGUGCU-3′ (SEQ ID NO: 1512)AAT-1353 19 nt Target #3: 5′-GCCGUGCAUAAGGCUGUGC-3′ (SEQ ID NO: 1710)AAT-1354 19 nt Target #1: 5′-GUGCAUAAGGCUGUGCUGA-3′ (SEQ ID NO: 1315)AAT-1354 19 nt Target #2: 5′-CGUGCAUAAGGCUGUGCUG-3′ (SEQ ID NO: 1513)AAT-1354 19 nt Target #3: 5′-CCGUGCAUAAGGCUGUGCU-3′ (SEQ ID NO: 1711)AAT-1355 19 nt Target #1: 5′-UGCAUAAGGCUGUGCUGAC-3′ (SEQ ID NO: 1316)AAT-1355 19 nt Target #2: 5′-GUGCAUAAGGCUGUGCUGA-3′ (SEQ ID NO: 1514)AAT-1355 19 nt Target #3: 5′-CGUGCAUAAGGCUGUGCUG-3′ (SEQ ID NO: 1712)AAT-1356 19 nt Target #1: 5′-GCAUAAGGCUGUGCUGACC-3′ (SEQ ID NO: 1317)AAT-1356 19 nt Target #2: 5′-UGCAUAAGGCUGUGCUGAC-3′ (SEQ ID NO: 1515)AAT-1356 19 nt Target #3: 5′-GUGCAUAAGGCUGUGCUGA-3′ (SEQ ID NO: 1713)AAT-1357 19 nt Target #1: 5′-CAUAAGGCUGUGCUGACCA-3′ (SEQ ID NO: 1318)AAT-1357 19 nt Target #2: 5′-GCAUAAGGCUGUGCUGACC-3′ (SEQ ID NO: 1516)AAT-1357 19 nt Target #3: 5′-UGCAUAAGGCUGUGCUGAC-3′ (SEQ ID NO: 1714)AAT-1358 19 nt Target #1: 5′-AUAAGGCUGUGCUGACCAU-3′ (SEQ ID NO: 1319)AAT-1358 19 nt Target #2: 5′-CAUAAGGCUGUGCUGACCA-3′ (SEQ ID NO: 1517)AAT-1358 19 nt Target #3: 5′-GCAUAAGGCUGUGCUGACC-3′ (SEQ ID NO: 1715)AAT-1359 19 nt Target #1: 5′-UAAGGCUGUGCUGACCAUC-3′ (SEQ ID NO: 1320)AAT-1359 19 nt Target #2: 5′-AUAAGGCUGUGCUGACCAU-3′ (SEQ ID NO: 1518)AAT-1359 19 nt Target #3: 5′-CAUAAGGCUGUGCUGACCA-3′ (SEQ ID NO: 1716)AAT-1360 19 nt Target #1: 5′-AAGGCUGUGCUGACCAUCG-3′ (SEQ ID NO: 1321)AAT-1360 19 nt Target #2: 5′-UAAGGCUGUGCUGACCAUC-3′ (SEQ ID NO: 1519)AAT-1360 19 nt Target #3: 5′-AUAAGGCUGUGCUGACCAU-3′ (SEQ ID NO: 1717)AAT-1361 19 nt Target #1: 5′-AGGCUGUGCUGACCAUCGA-3′ (SEQ ID NO: 1322)AAT-1361 19 nt Target #2: 5′-AAGGCUGUGCUGACCAUCG-3′ (SEQ ID NO: 1520)AAT-1361 19 nt Target #3: 5′-UAAGGCUGUGCUGACCAUC-3′ (SEQ ID NO: 1718)AAT-1390 19 nt Target #1: 5′-ACUGAAGCUGCUGGGGCCA-3′ (SEQ ID NO: 1323)AAT-1390 19 nt Target #2: 5′-GACUGAAGCUGCUGGGGCC-3′ (SEQ ID NO: 1521)AAT-1390 19 nt Target #3: 5′-GGACUGAAGCUGCUGGGGC-3′ (SEQ ID NO: 1719)AAT-1391 19 nt Target #1: 5′-CUGAAGCUGCUGGGGCCAU-3′ (SEQ ID NO: 1324)AAT-1391 19 nt Target #2: 5′-ACUGAAGCUGCUGGGGCCA-3′ (SEQ ID NO: 1522)AAT-1391 19 nt Target #3: 5′-GACUGAAGCUGCUGGGGCC-3′ (SEQ ID NO: 1720)AAT-1392 19 nt Target #1: 5′-UGAAGCUGCUGGGGCCAUG-3′ (SEQ ID NO: 1325)AAT-1392 19 nt Target #2: 5′-CUGAAGCUGCUGGGGCCAU-3′ (SEQ ID NO: 1523)AAT-1392 19 nt Target #3: 5′-ACUGAAGCUGCUGGGGCCA-3′ (SEQ ID NO: 1721)AAT-1393 19 nt Target #1: 5′-GAAGCUGCUGGGGCCAUGU-3′ (SEQ ID NO: 1326)AAT-1393 19 nt Target #2: 5′-UGAAGCUGCUGGGGCCAUG-3′ (SEQ ID NO: 1524)AAT-1393 19 nt Target #3: 5′-CUGAAGCUGCUGGGGCCAU-3′ (SEQ ID NO: 1722)AAT-1394 19 nt Target #1: 5′-AAGCUGCUGGGGCCAUGUU-3′ (SEQ ID NO: 1327)AAT-1394 19 nt Target #2: 5′-GAAGCUGCUGGGGCCAUGU-3′ (SEQ ID NO: 1525)AAT-1394 19 nt Target #3: 5′-UGAAGCUGCUGGGGCCAUG-3′ (SEQ ID NO: 1723)AAT-1395 19 nt Target #1: 5′-AGCUGCUGGGGCCAUGUUU-3′ (SEQ ID NO: 1328)AAT-1395 19 nt Target #2: 5′-AAGCUGCUGGGGCCAUGUU-3′ (SEQ ID NO: 1526)AAT-1395 19 nt Target #3: 5′-GAAGCUGCUGGGGCCAUGU-3′ (SEQ ID NO: 1724)AAT-1405 19 nt Target #1: 5′-GCCAUGUUUUUAGAGGCCA-3′ (SEQ ID NO: 1329)AAT-1405 19 nt Target #2: 5′-GGCCAUGUUUUUAGAGGCC-3′ (SEQ ID NO: 1527)AAT-1405 19 nt Target #3: 5′-GGGCCAUGUUUUUAGAGGC-3′ (SEQ ID NO: 1725)AAT-1406 19 nt Target #1: 5′-CCAUGUUUUUAGAGGCCAU-3′ (SEQ ID NO: 1330)AAT-1406 19 nt Target #2: 5′-GCCAUGUUUUUAGAGGCCA-3′ (SEQ ID NO: 1528)AAT-1406 19 nt Target #3: 5′-GGCCAUGUUUUUAGAGGCC-3′ (SEQ ID NO: 1726)AAT-1407 19 nt Target #1: 5′-CAUGUUUUUAGAGGCCAUA-3′ (SEQ ID NO: 1331)AAT-1407 19 nt Target #2: 5′-CCAUGUUUUUAGAGGCCAU-3′ (SEQ ID NO: 1529)AAT-1407 19 nt Target #3: 5′-GCCAUGUUUUUAGAGGCCA-3′ (SEQ ID NO: 1727)AAT-1408 19 nt Target #1: 5′-AUGUUUUUAGAGGCCAUAC-3′ (SEQ ID NO: 1332)AAT-1408 19 nt Target #2: 5′-CAUGUUUUUAGAGGCCAUA-3′ (SEQ ID NO: 1530)AAT-1408 19 nt Target #3: 5′-CCAUGUUUUUAGAGGCCAU-3′ (SEQ ID NO: 1728)AAT-1409 19 nt Target #1: 5′-UGUUUUUAGAGGCCAUACC-3′ (SEQ ID NO: 1333)AAT-1409 19 nt Target #2: 5′-AUGUUUUUAGAGGCCAUAC-3′ (SEQ ID NO: 1531)AAT-1409 19 nt Target #3: 5′-CAUGUUUUUAGAGGCCAUA-3′ (SEQ ID NO: 1729)AAT-1410 19 nt Target #1: 5′-GUUUUUAGAGGCCAUACCC-3′ (SEQ ID NO: 1334)AAT-1410 19 nt Target #2: 5′-UGUUUUUAGAGGCCAUACC-3′ (SEQ ID NO: 1532)AAT-1410 19 nt Target #3: 5′-AUGUUUUUAGAGGCCAUAC-3′ (SEQ ID NO: 1730)AAT-1411 19 nt Target #1: 5′-UUUUUAGAGGCCAUACCCA-3′ (SEQ ID NO: 1335)AAT-1411 19 nt Target #2: 5′-GUUUUUAGAGGCCAUACCC-3′ (SEQ ID NO: 1533)AAT-1411 19 nt Target #3: 5′-UGUUUUUAGAGGCCAUACC-3′ (SEQ ID NO: 1731)AAT-1412 19 nt Target #1: 5′-UUUUAGAGGCCAUACCCAU-3′ (SEQ ID NO: 1336)AAT-1412 19 nt Target #2: 5′-UUUUUAGAGGCCAUACCCA-3′ (SEQ ID NO: 1534)AAT-1412 19 nt Target #3: 5′-GUUUUUAGAGGCCAUACCC-3′ (SEQ ID NO: 1732)AAT-1413 19 nt Target #1: 5′-UUUAGAGGCCAUACCCAUG-3′ (SEQ ID NO: 1337)AAT-1413 19 nt Target #2: 5′-UUUUAGAGGCCAUACCCAU-3′ (SEQ ID NO: 1535)AAT-1413 19 nt Target #3: 5′-UUUUUAGAGGCCAUACCCA-3′ (SEQ ID NO: 1733)AAT-1414 19 nt Target #1: 5′-UUAGAGGCCAUACCCAUGU-3′ (SEQ ID NO: 1338)AAT-1414 19 nt Target #2: 5′-UUUAGAGGCCAUACCCAUG-3′ (SEQ ID NO: 1536)AAT-1414 19 nt Target #3: 5′-UUUUAGAGGCCAUACCCAU-3′ (SEQ ID NO: 1734)AAT-1415 19 nt Target #1: 5′-UAGAGGCCAUACCCAUGUC-3′ (SEQ ID NO: 1339)AAT-1415 19 nt Target #2: 5′-UUAGAGGCCAUACCCAUGU-3′ (SEQ ID NO: 1537)AAT-1415 19 nt Target #3: 5′-UUUAGAGGCCAUACCCAUG-3′ (SEQ ID NO: 1735)AAT-1416 19 nt Target #1: 5′-AGAGGCCAUACCCAUGUCU-3′ (SEQ ID NO: 1340)AAT-1416 19 nt Target #2: 5′-UAGAGGCCAUACCCAUGUC-3′ (SEQ ID NO: 1538)AAT-1416 19 nt Target #3: 5′-UUAGAGGCCAUACCCAUGU-3′ (SEQ ID NO: 1736)AAT-1452 19 nt Target #1: 5′-GUUCAACAAACCCUUUGUC-3′ (SEQ ID NO: 1341)AAT-1452 19 nt Target #2: 5′-AGUUCAACAAACCCUUUGU-3′ (SEQ ID NO: 1539)AAT-1452 19 nt Target #3: 5′-AAGUUCAACAAACCCUUUG-3′ (SEQ ID NO: 1737)AAT-1453 19 nt Target #1: 5′-UUCAACAAACCCUUUGUCU-3′ (SEQ ID NO: 1342)AAT-1453 19 nt Target #2: 5′-GUUCAACAAACCCUUUGUC-3′ (SEQ ID NO: 1540)AAT-1453 19 nt Target #3: 5′-AGUUCAACAAACCCUUUGU-3′ (SEQ ID NO: 1738)AAT-1454 19 nt Target #1: 5′-UCAACAAACCCUUUGUCUU-3′ (SEQ ID NO: 1343)AAT-1454 19 nt Target #2: 5′-UUCAACAAACCCUUUGUCU-3′ (SEQ ID NO: 1541)AAT-1454 19 nt Target #3: 5′-GUUCAACAAACCCUUUGUC-3′ (SEQ ID NO: 1739)AAT-1455 19 nt Target #1: 5′-CAACAAACCCUUUGUCUUC-3′ (SEQ ID NO: 1344)AAT-1455 19 nt Target #2: 5′-UCAACAAACCCUUUGUCUU-3′ (SEQ ID NO: 1542)AAT-1455 19 nt Target #3: 5′-UUCAACAAACCCUUUGUCU-3′ (SEQ ID NO: 1740)AAT-1456 19 nt Target #1: 5′-AACAAACCCUUUGUCUUCU-3′ (SEQ ID NO: 1345)AAT-1456 19 nt Target #2: 5′-CAACAAACCCUUUGUCUUC-3′ (SEQ ID NO: 1543)AAT-1456 19 nt Target #3: 5′-UCAACAAACCCUUUGUCUU-3′ (SEQ ID NO: 1741)AAT-1457 19 nt Target #1: 5′-ACAAACCCUUUGUCUUCUU-3′ (SEQ ID NO: 1346)AAT-1457 19 nt Target #2: 5′-AACAAACCCUUUGUCUUCU-3′ (SEQ ID NO: 1544)AAT-1457 19 nt Target #3: 5′-CAACAAACCCUUUGUCUUC-3′ (SEQ ID NO: 1742)AAT-1458 19 nt Target #1: 5′-CAAACCCUUUGUCUUCUUA-3′ (SEQ ID NO: 1347)AAT-1458 19 nt Target #2: 5′-ACAAACCCUUUGUCUUCUU-3′ (SEQ ID NO: 1545)AAT-1458 19 nt Target #3: 5′-AACAAACCCUUUGUCUUCU-3′ (SEQ ID NO: 1743)AAT-1459 19 nt Target #1: 5′-AAACCCUUUGUCUUCUUAA-3′ (SEQ ID NO: 1348)AAT-1459 19 nt Target #2: 5′-CAAACCCUUUGUCUUCUUA-3′ (SEQ ID NO: 1546)AAT-1459 19 nt Target #3: 5′-ACAAACCCUUUGUCUUCUU-3′ (SEQ ID NO: 1744)AAT-1460 19 nt Target #1: 5′-AACCCUUUGUCUUCUUAAU-3′ (SEQ ID NO: 1349)AAT-1460 19 nt Target #2: 5′-AAACCCUUUGUCUUCUUAA-3′ (SEQ ID NO: 1547)AAT-1460 19 nt Target #3: 5′-CAAACCCUUUGUCUUCUUA-3′ (SEQ ID NO: 1745)AAT-1489 19 nt Target #1: 5′-AAUACCAAGUCUCCCCUCU-3′ (SEQ ID NO: 1350)AAT-1489 19 nt Target #2: 5′-AAAUACCAAGUCUCCCCUC-3′ (SEQ ID NO: 1548)AAT-1489 19 nt Target #3: 5′-AAAAUACCAAGUCUCCCCU-3′ (SEQ ID NO: 1746)AAT-1490 19 nt Target #1: 5′-AUACCAAGUCUCCCCUCUU-3′ (SEQ ID NO: 1351)AAT-1490 19 nt Target #2: 5′-AAUACCAAGUCUCCCCUCU-3′ (SEQ ID NO: 1549)AAT-1490 19 nt Target #3: 5′-AAAUACCAAGUCUCCCCUC-3′ (SEQ ID NO: 1747)AAT-1491 19 nt Target #1: 5′-UACCAAGUCUCCCCUCUUC-3′ (SEQ ID NO: 1352)AAT-1491 19 nt Target #2: 5′-AUACCAAGUCUCCCCUCUU-3′ (SEQ ID NO: 1550)AAT-1491 19 nt Target #3: 5′-AAUACCAAGUCUCCCCUCU-3′ (SEQ ID NO: 1748)AAT-1492 19 nt Target #1: 5′-ACCAAGUCUCCCCUCUUCA-3′ (SEQ ID NO: 1353)AAT-1492 19 nt Target #2: 5′-UACCAAGUCUCCCCUCUUC-3′ (SEQ ID NO: 1551)AAT-1492 19 nt Target #3: 5′-AUACCAAGUCUCCCCUCUU-3′ (SEQ ID NO: 1749)AAT-1493 19 nt Target #1: 5′-CCAAGUCUCCCCUCUUCAU-3′ (SEQ ID NO: 1354)AAT-1493 19 nt Target #2: 5′-ACCAAGUCUCCCCUCUUCA-3′ (SEQ ID NO: 1552)AAT-1493 19 nt Target #3: 5′-UACCAAGUCUCCCCUCUUC-3′ (SEQ ID NO: 1750)AAT-1494 19 nt Target #1: 5′-CAAGUCUCCCCUCUUCAUG-3′ (SEQ ID NO: 1355)AAT-1494 19 nt Target #2: 5′-CCAAGUCUCCCCUCUUCAU-3′ (SEQ ID NO: 1553)AAT-1494 19 nt Target #3: 5′-ACCAAGUCUCCCCUCUUCA-3′ (SEQ ID NO: 1751)AAT-1495 19 nt Target #1: 5′-AAGUCUCCCCUCUUCAUGG-3′ (SEQ ID NO: 1356)AAT-1495 19 nt Target #2: 5′-CAAGUCUCCCCUCUUCAUG-3′ (SEQ ID NO: 1554)AAT-1495 19 nt Target #3: 5′-CCAAGUCUCCCCUCUUCAU-3′ (SEQ ID NO: 1752)AAT-1496 19 nt Target #1: 5′-AGUCUCCCCUCUUCAUGGG-3′ (SEQ ID NO: 1357)AAT-1496 19 nt Target #2: 5′-AAGUCUCCCCUCUUCAUGG-3′ (SEQ ID NO: 1555)AAT-1496 19 nt Target #3: 5′-CAAGUCUCCCCUCUUCAUG-3′ (SEQ ID NO: 1753)AAT-1497 19 nt Target #1: 5′-GUCUCCCCUCUUCAUGGGA-3′ (SEQ ID NO: 1358)AAT-1497 19 nt Target #2: 5′-AGUCUCCCCUCUUCAUGGG-3′ (SEQ ID NO: 1556)AAT-1497 19 nt Target #3: 5′-AAGUCUCCCCUCUUCAUGG-3′ (SEQ ID NO: 1754)AAT-1499 19 nt Target #1: 5′-CUCCCCUCUUCAUGGGAAA-3′ (SEQ ID NO: 1359)AAT-1499 19 nt Target #2: 5′-UCUCCCCUCUUCAUGGGAA-3′ (SEQ ID NO: 1557)AAT-1499 19 nt Target #3: 5′-GUCUCCCCUCUUCAUGGGA-3′ (SEQ ID NO: 1755)AAT-1501 19 nt Target #1: 5′-CCCCUCUUCAUGGGAAAAG-3′ (SEQ ID NO: 1360)AAT-1501 19 nt Target #2: 5′-UCCCCUCUUCAUGGGAAAA-3′ (SEQ ID NO: 1558)AAT-1501 19 nt Target #3: 5′-CUCCCCUCUUCAUGGGAAA-3′ (SEQ ID NO: 1756)AAT-1502 19 nt Target #1: 5′-CCCUCUUCAUGGGAAAAGU-3′ (SEQ ID NO: 1361)AAT-1502 19 nt Target #2: 5′-CCCCUCUUCAUGGGAAAAG-3′ (SEQ ID NO: 1559)AAT-1502 19 nt Target #3: 5′-UCCCCUCUUCAUGGGAAAA-3′ (SEQ ID NO: 1757)AAT-1503 19 nt Target #1: 5′-CCUCUUCAUGGGAAAAGUG-3′ (SEQ ID NO: 1362)AAT-1503 19 nt Target #2: 5′-CCCUCUUCAUGGGAAAAGU-3′ (SEQ ID NO: 1560)AAT-1503 19 nt Target #3: 5′-CCCCUCUUCAUGGGAAAAG-3′ (SEQ ID NO: 1758)AAT-1504 19 nt Target #1: 5′-CUCUUCAUGGGAAAAGUGG-3′ (SEQ ID NO: 1363)AAT-1504 19 nt Target #2: 5′-CCUCUUCAUGGGAAAAGUG-3′ (SEQ ID NO: 1561)AAT-1504 19 nt Target #3: 5′-CCCUCUUCAUGGGAAAAGU-3′ (SEQ ID NO: 1759)AAT-1505 19 nt Target #1: 5′-UCUUCAUGGGAAAAGUGGU-3′ (SEQ ID NO: 1364)AAT-1505 19 nt Target #2: 5′-CUCUUCAUGGGAAAAGUGG-3′ (SEQ ID NO: 1562)AAT-1505 19 nt Target #3: 5′-CCUCUUCAUGGGAAAAGUG-3′ (SEQ ID NO: 1760)AAT-1506 19 nt Target #1: 5′-CUUCAUGGGAAAAGUGGUG-3′ (SEQ ID NO: 1365)AAT-1506 19 nt Target #2: 5′-UCUUCAUGGGAAAAGUGGU-3′ (SEQ ID NO: 1563)AAT-1506 19 nt Target #3: 5′-CUCUUCAUGGGAAAAGUGG-3′ (SEQ ID NO: 1761)AAT-1507 19 nt Target #1: 5′-UUCAUGGGAAAAGUGGUGA-3′ (SEQ ID NO: 1366)AAT-1507 19 nt Target #2: 5′-CUUCAUGGGAAAAGUGGUG-3′ (SEQ ID NO: 1564)AAT-1507 19 nt Target #3: 5′-UCUUCAUGGGAAAAGUGGU-3′ (SEQ ID NO: 1762)AAT-1508 19 nt Target #1: 5′-UCAUGGGAAAAGUGGUGAA-3′ (SEQ ID NO: 1367)AAT-1508 19 nt Target #2: 5′-UUCAUGGGAAAAGUGGUGA-3′ (SEQ ID NO: 1565)AAT-1508 19 nt Target #3: 5′-CUUCAUGGGAAAAGUGGUG-3′ (SEQ ID NO: 1763)AAT-1509 19 nt Target #1: 5′-CAUGGGAAAAGUGGUGAAU-3′ (SEQ ID NO: 1368)AAT-1509 19 nt Target #2: 5′-UCAUGGGAAAAGUGGUGAA-3′ (SEQ ID NO: 1566)AAT-1509 19 nt Target #3: 5′-UUCAUGGGAAAAGUGGUGA-3′ (SEQ ID NO: 1764)AAT-1510 19 nt Target #1: 5′-AUGGGAAAAGUGGUGAAUC-3′ (SEQ ID NO: 1369)AAT-1510 19 nt Target #2: 5′-CAUGGGAAAAGUGGUGAAU-3′ (SEQ ID NO: 1567)AAT-1510 19 nt Target #3: 5′-UCAUGGGAAAAGUGGUGAA-3′ (SEQ ID NO: 1765)AAT-1511 19 nt Target #1: 5′-UGGGAAAAGUGGUGAAUCC-3′ (SEQ ID NO: 1370)AAT-1511 19 nt Target #2: 5′-AUGGGAAAAGUGGUGAAUC-3′ (SEQ ID NO: 1568)AAT-1511 19 nt Target #3: 5′-CAUGGGAAAAGUGGUGAAU-3′ (SEQ ID NO: 1766)AAT-1512 19 nt Target #1: 5′-GGGAAAAGUGGUGAAUCCC-3′ (SEQ ID NO: 1371)AAT-1512 19 nt Target #2: 5′-UGGGAAAAGUGGUGAAUCC-3′ (SEQ ID NO: 1569)AAT-1512 19 nt Target #3: 5′-AUGGGAAAAGUGGUGAAUC-3′ (SEQ ID NO: 1767)AAT-1513 19 nt Target #1: 5′-GGAAAAGUGGUGAAUCCCA-3′ (SEQ ID NO: 1372)AAT-1513 19 nt Target #2: 5′-GGGAAAAGUGGUGAAUCCC-3′ (SEQ ID NO: 1570)AAT-1513 19 nt Target #3: 5′-UGGGAAAAGUGGUGAAUCC-3′ (SEQ ID NO: 1768)AAT-1514 19 nt Target #1: 5′-GAAAAGUGGUGAAUCCCAC-3′ (SEQ ID NO: 1373)AAT-1514 19 nt Target #2: 5′-GGAAAAGUGGUGAAUCCCA-3′ (SEQ ID NO: 1571)AAT-1514 19 nt Target #3: 5′-GGGAAAAGUGGUGAAUCCC-3′ (SEQ ID NO: 1769)AAT-1515 19 nt Target #1: 5′-AAAAGUGGUGAAUCCCACC-3′ (SEQ ID NO: 1374)AAT-1515 19 nt Target #2: 5′-GAAAAGUGGUGAAUCCCAC-3′ (SEQ ID NO: 1572)AAT-1515 19 nt Target #3: 5′-GGAAAAGUGGUGAAUCCCA-3′ (SEQ ID NO: 1770)AAT-1516 19 nt Target #1: 5′-AAAGUGGUGAAUCCCACCC-3′ (SEQ ID NO: 1375)AAT-1516 19 nt Target #2: 5′-AAAAGUGGUGAAUCCCACC-3′ (SEQ ID NO: 1573)AAT-1516 19 nt Target #3: 5′-GAAAAGUGGUGAAUCCCAC-3′ (SEQ ID NO: 1771)AAT-1517 19 nt Target #1: 5′-AAGUGGUGAAUCCCACCCA-3′ (SEQ ID NO: 1376)AAT-1517 19 nt Target #2: 5′-AAAGUGGUGAAUCCCACCC-3′ (SEQ ID NO: 1574)AAT-1517 19 nt Target #3: 5′-AAAAGUGGUGAAUCCCACC-3′ (SEQ ID NO: 1772)AAT-2872 19 nt Target #1: 5′-CGAUAGUUCAAAAUGGUGA-3′ (SEQ ID NO: 1377)AAT-2872 19 nt Target #2: 5′-UCGAUAGUUCAAAAUGGUG-3′ (SEQ ID NO: 1575)AAT-2872 19 nt Target #3: 5′-UUCGAUAGUUCAAAAUGGU-3′ (SEQ ID NO: 1773)AAT-2880 19 nt Target #1: 5′-CAAAAUGGUGAAAUUAGCA-3′ (SEQ ID NO: 1378)AAT-2880 19 nt Target #2: 5′-UCAAAAUGGUGAAAUUAGC-3′ (SEQ ID NO: 1576)AAT-2880 19 nt Target #3: 5′-UUCAAAAUGGUGAAAUUAG-3′ (SEQ ID NO: 1774)AAT-3167 19 nt Target #1: 5′-UUGGUAUGAUGUUCAAGUU-3′ (SEQ ID NO: 1379)AAT-3167 19 nt Target #2: 5′-GUUGGUAUGAUGUUCAAGU-3′ (SEQ ID NO: 1577)AAT-3167 19 nt Target #3: 5′-AGUUGGUAUGAUGUUCAAG-3′ (SEQ ID NO: 1775)AAT-3169 19 nt Target #1: 5′-GGUAUGAUGUUCAAGUUAG-3′ (SEQ ID NO: 1380)AAT-3169 19 nt Target #2: 5′-UGGUAUGAUGUUCAAGUUA-3′ (SEQ ID NO: 1578)AAT-3169 19 nt Target #3: 5′-UUGGUAUGAUGUUCAAGUU-3′ (SEQ ID NO: 1776)AAT-3170 19 nt Target #1: 5′-GUAUGAUGUUCAAGUUAGA-3′ (SEQ ID NO: 1381)AAT-3170 19 nt Target #2: 5′-GGUAUGAUGUUCAAGUUAG-3′ (SEQ ID NO: 1579)AAT-3170 19 nt Target #3: 5′-UGGUAUGAUGUUCAAGUUA-3′ (SEQ ID NO: 1777)AAT-3172 19 nt Target #1: 5′-AUGAUGUUCAAGUUAGAUA-3′ (SEQ ID NO: 1382)AAT-3172 19 nt Target #2: 5′-UAUGAUGUUCAAGUUAGAU-3′ (SEQ ID NO: 1580)AAT-3172 19 nt Target #3: 5′-GUAUGAUGUUCAAGUUAGA-3′ (SEQ ID NO: 1778)AAT-3175 19 nt Target #1: 5′-AUGUUCAAGUUAGAUAACA-3′ (SEQ ID NO: 1383)AAT-3175 19 nt Target #2: 5′-GAUGUUCAAGUUAGAUAAC-3′ (SEQ ID NO: 1581)AAT-3175 19 nt Target #3: 5′-UGAUGUUCAAGUUAGAUAA-3′ (SEQ ID NO: 1779)AAT-3180 19 nt Target #1: 5′-CAAGUUAGAUAACAAAAUG-3′ (SEQ ID NO: 1384)AAT-3180 19 nt Target #2: 5′-UCAAGUUAGAUAACAAAAU-3′ (SEQ ID NO: 1582)AAT-3180 19 nt Target #3: 5′-UUCAAGUUAGAUAACAAAA-3′ (SEQ ID NO: 1780)AAT-3181 19 nt Target #1: 5′-AAGUUAGAUAACAAAAUGU-3′ (SEQ ID NO: 1385)AAT-3181 19 nt Target #2: 5′-CAAGUUAGAUAACAAAAUG-3′ (SEQ ID NO: 1583)AAT-3181 19 nt Target #3: 5′-UCAAGUUAGAUAACAAAAU-3′ (SEQ ID NO: 1781)AAT-3182 19 nt Target #1: 5′-AGUUAGAUAACAAAAUGUU-3′ (SEQ ID NO: 1386)AAT-3182 19 nt Target #2: 5′-AAGUUAGAUAACAAAAUGU-3′ (SEQ ID NO: 1584)AAT-3182 19 nt Target #3: 5′-CAAGUUAGAUAACAAAAUG-3′ (SEQ ID NO: 1782)

TABLE 7Additional Human Anti-α-1 antitrypsin DsiRNA Agents (Asymmetries)  5′-GCGUUUAGGCAUGUUUAACAUCCag-3′ (SEQ ID NO: 1783)3′-UUCGCAAAUCCGUACAAAUUGUAGGUC-5′ (SEQ ID NO: 1814)AAT-1023 Target: 5′-AAGCGTTTAGGCATGTTTAACATCCAG-3′ (SEQ ID NO: 1845)  5′-CGUUUAGGCAUGUUUAACAUCCAgc-3′ (SEQ ID NO: 1784)3′-UCGCAAAUCCGUACAAAUUGUAGGUCG-5′ (SEQ ID NO: 1815)AAT-1024 Target: 5′-AGCGTTTAGGCATGTTTAACATCCAGC-3′ (SEQ ID NO: 1846)  5′-GGCCAUGUUUUUAGAGGCCAUACCC-3′ (SEQ ID NO: 1785)3′-CCCCGGUACAAAAAUCUCCGGUAUGGG-5′ (SEQ ID NO: 1816)AAT-1404 Target: 5′-GGGGCCATGTTTTTAGAGGCCATACCC-3′ (SEQ ID NO: 1847)  5′-ACCCUUUGUCUUCUUAAUGAUUGaa-3′ (SEQ ID NO: 1786)3′-UUUGGGAAACAGAAGAAUUACUAACUU-5′ (SEQ ID NO: 1817)AAT-1461 Target: 5′-AAACCCTTTGTCTTCTTAATGATTGAA-3′ (SEQ ID NO: 1848)  5′-CCCUUUGUCUUCUUAAUGAUUGAac-3′ (SEQ ID NO: 1787)3′-UUGGGAAACAGAAGAAUUACUAACUUG-5′ (SEQ ID NO: 1818)AAT-1462 Target: 5′-AACCCTTTGTCTTCTTAATGATTGAAC-3′ (SEQ ID NO: 1849)  5′-CCUUUGUCUUCUUAAUGAUUGAAca-3′ (SEQ ID NO: 1788)3′-UGGGAAACAGAAGAAUUACUAACUUGU-5′ (SEQ ID NO: 1819)AAT-1463 Target: 5′-ACCCTTTGTCTTCTTAATGATTGAACA-3′ (SEQ ID NO: 1850)  5′-CUUUGUCUUCUUAAUGAUUGAACaa-3′ (SEQ ID NO: 1789)3′-GGGAAACAGAAGAAUUACUAACUUGUU-5′ (SEQ ID NO: 1820)AAT-1464 Target: 5′-CCCTTTGTCTTCTTAATGATTGAACAA-3′ (SEQ ID NO: 1851)  5′-UUUGUCUUCUUAAUGAUUGAACAaa-3′ (SEQ ID NO: 1790)3′-GGAAACAGAAGAAUUACUAACUUGUUU-5′ (SEQ ID NO: 1821)AAT-1465 Target: 5′-CCTTTGTCTTCTTAATGATTGAACAAA-3′ (SEQ ID NO: 1852)  5′-UUGUCUUCUUAAUGAUUGAACAAaa-3′ (SEQ ID NO: 1791)3′-GAAACAGAAGAAUUACUAACUUGUUUU-5′ (SEQ ID NO: 1822)AAT-1466 Target: 5′-CTTTGTCTTCTTAATGATTGAACAAAA-3′ (SEQ ID NO: 1853)  5′-UGUCUUCUUAAUGAUUGAACAAAat-3′ (SEQ ID NO: 1792)3′-AAACAGAAGAAUUACUAACUUGUUUUA-5′ (SEQ ID NO: 1823)AAT-1467 Target: 5′-TTTGTCTTCTTAATGATTGAACAAAAT-3′ (SEQ ID NO: 1854)  5′-GUCUUCUUAAUGAUUGAACAAAAta-3′ (SEQ ID NO: 1793)3′-AACAGAAGAAUUACUAACUUGUUUUAU-5′ (SEQ ID NO: 1824)AAT-1468 Target: 5′-TTGTCTTCTTAATGATTGAACAAAATA-3′ (SEQ ID NO: 1855)  5′-UCUUCUUAAUGAUUGAACAAAAUac-3′ (SEQ ID NO: 1794)3′-ACAGAAGAAUUACUAACUUGUUUUAUG-5′ (SEQ ID NO: 1825)AAT-1469 Target: 5′-TGTCTTCTTAATGATTGAACAAAATAC-3′ (SEQ ID NO: 1856)  5′-CUUCUUAAUGAUUGAACAAAAUAcc-3′ (SEQ ID NO: 1795)3′-CAGAAGAAUUACUAACUUGUUUUAUGG-5′ (SEQ ID NO: 1826)AAT-1470 Target: 5′-GTCTTCTTAATGATTGAACAAAATACC-3′ (SEQ ID NO: 1857)  5′-UUCUUAAUGAUUGAACAAAAUACca-3′ (SEQ ID NO: 1796)3′-AGAAGAAUUACUAACUUGUUUUAUGGU-5′ (SEQ ID NO: 1827)AAT-1471 Target: 5′-TCTTCTTAATGATTGAACAAAATACCA-3′ (SEQ ID NO: 1858)  5′-UCUUAAUGAUUGAACAAAAUACCaa-3′ (SEQ ID NO: 1797)3′-GAAGAAUUACUAACUUGUUUUAUGGUU-5′ (SEQ ID NO: 1828)AAT-1472 Target: 5′-CTTCTTAATGATTGAACAAAATACCAA-3′ (SEQ ID NO: 1859)  5′-CUUAAUGAUUGAACAAAAUACCAag-3′ (SEQ ID NO: 1798)3′-AAGAAUUACUAACUUGUUUUAUGGUUC-5′ (SEQ ID NO: 1829)AAT-1473 Target: 5′-TTCTTAATGATTGAACAAAATACCAAG-3′ (SEQ ID NO: 1860)  5′-UUAAUGAUUGAACAAAAUACCAAgt-3′ (SEQ ID NO: 1799)3′-AGAAUUACUAACUUGUUUUAUGGUUCA-5′ (SEQ ID NO: 1830)AAT-1474 Target: 5′-TCTTAATGATTGAACAAAATACCAAGT-3′ (SEQ ID NO: 1861)  5′-UAAUGAUUGAACAAAAUACGAAGtC-3′ (SEQ ID NO: 1800)3′-GAAUUACUAACUUGUUUUAUGGUUCAG-5′ (SEQ ID NO: 1831)AAT-1475 Target: 5′-CTTAATGATTGAACAAAATACCAAGTC-3′ (SEQ ID NO: 1862)  5′-AAUGAUUGAACAAAAUACCAAGUct-3′ (SEQ ID NO: 1801)3′-AAUUACUAACUUGUUUUAUGGUUCAGA-5′ (SEQ ID NO: 1832)AAT-1476 Target: 5′-TTAATGATTGAACAAAATACCAAGTCT-3′ (SEQ ID NO: 1863)  5′-AUGAUUGAACAAAAUACGAAGUCtC-3′ (SEQ ID NO: 1802)3′-AUUACUAACUUGUUUUAUGGUUCAGAG-5′ (SEQ ID NO: 1833)AAT-1477 Target: 5′-TAATGATTGAACAAAATACCAAGTCTC-3′ (SEQ ID NO: 1864)  5′-UGAUUGAACAAAAUACCAAGUCUcC-3′ (SEQ ID NO: 1803)3′-UUACUAACUUGUUUUAUGGUUCAGAGG-5′ (SEQ ID NO: 1834)AAT-1478 Target: 5′-AATGATTGAACAAAATACCAAGTCTCC-3′ (SEQ ID NO: 1865)  5′-GAUUGAACAAAAUACCAAGUCUCcC-3′ (SEQ ID NO: 1804)3′-UACUAACUUGUUUUAUGGUUCAGAGGG-5′ (SEQ ID NO: 1835)AAT-1479 Target: 5′-ATGATTGAACAAAATACCAAGTCTCCC-3′ (SEQ ID NO: 1866)  5′-AUUGAACAAAAUACCAAGUCUCCcC-3′ (SEQ ID NO: 1805)3′-ACUAACUUGUUUUAUGGUUCAGAGGGG-5′ (SEQ ID NO: 1836)AAT-1480 Target: 5′-TGATTGAACAAAATACCAAGTCTCCCC-3′ (SEQ ID NO: 1867)  5′-UUGAACAAAAUACCAAGUCUCCCct-3′ (SEQ ID NO: 1806)3′-CUAACUUGUUUUAUGGUUCAGAGGGGA-5′ (SEQ ID NO: 1837)AAT-1481 Target: 5′-GATTGAACAAAATACCAAGTCTCCCCT-3′ (SEQ ID NO: 1868)  5′-UGAACAAAAUACCAAGUCUCCCCtc-3′ (SEQ ID NO: 1807)3′-UAACUUGUUUUAUGGUUCAGAGGGGAG-5′ (SEQ ID NO: 1838)AAT-1482 Target: 5′-ATTGAACAAAATACCAAGTCTCCCCTC-3′ (SEQ ID NO: 1869)  5′-GAACAAAAUACCAAGUCUCCCCUct-3′ (SEQ ID NO: 1808)3′-AACUUGUUUUAUGGUUCAGAGGGGAGA-5′ (SEQ ID NO: 1839)AAT-1483 Target: 5′-TTGAACAAAATACCAAGTCTCCCCTCT-3′ (SEQ ID NO: 1870)  5′-AACAAAAUACCAAGUCUCCCCUCtt-3′ (SEQ ID NO: 1809)3′-ACUUGUUUUAUGGUUCAGAGGGGAGAA-5′ (SEQ ID NO: 1840)AAT-1484 Target: 5′-TGAACAAAATACCAAGTCTCCCCTCTT-3′ (SEQ ID NO: 1871)  5′-ACAAAAUACCAAGUCUCCCCUCUtc-3′ (SEQ ID NO: 1810)3′-CUUGUUUUAUGGUUCAGAGGGGAGAAG-5′ (SEQ ID NO: 1841)AAT-1485 Target: 5′-GAACAAAATACCAAGTCTCCCCTCTTC-3′ (SEQ ID NO: 1872)  5′-CAAAAUACCAAGUCUCCCCUCUUca-3′ (SEQ ID NO: 1811)3′-UUGUUUUAUGGUUCAGAGGGGAGAAGU-5′ (SEQ ID NO: 1842)AAT-1486 Target: 5′-AACAAAATACCAAGTCTCCCCTCTTCA-3′ (SEQ ID NO: 1873)  5′-AAAAUACCAAGUCUCCCCUCUUCat-3′ (SEQ ID NO: 1812)3′-UGUUUUAUGGUUCAGAGGGGAGAAGUA-5′ (SEQ ID NO: 1843)AAT-1487 Target: 5′-ACAAAATACCAAGTCTCCCCTCTTCAT-3′ (SEQ ID NO: 1874)  5′-AAAUACCAAGUCUCCCCUCUUCAtg-3′ (SEQ ID NO: 1813)3′-GUUUUAUGGUUCAGAGGGGAGAAGUAC-5′ (SEQ ID NO: 1844)AAT-1488 Target: 5′-CAAAATACCAAGTCTCCCCTCTTCATG-3′ (SEQ ID NO: 1875)

TABLE 8Additional Human Anti-α-1 antitrypsin DsiRNAs, Unmodified Duplexes(Asymmetries)   5′-GCGUUUAGGCAUGUUUAACAUCCAG-3′ (SEQ ID NO: 1876)3′-UUCGCAAAUCCGUACAAAUUGUAGGUC-5′ (SEQ ID NO: 1814)AAT-1023 Target: 5′-AAGCGTTTAGGCATGTTTAACATCCAG-3′ (SEQ ID NO: 1845)  5′-CGUUUAGGCAUGUUUAACAUCCAGC-3′ (SEQ ID NO: 1877)3′-UCGCAAAUCCGUACAAAUUGUAGGUCG-5′ (SEQ ID NO: 1815)AAT-1024 Target: 5′-AGCGTTTAGGCATGTTTAACATCCAGC-3′ (SEQ ID NO: 1846)  5′-GGCCAUGUUUUUAGAGGCCAUACCC-3′ (SEQ ID NO: 1878)3′-CCCCGGUACAAAAAUCUCCGGUAUGGG-5′(SEQ ID NO: 1816)AAT-1404 Target: 5′-GGGGCCATGTTTTTAGAGGCCATACCC-3′ (SEQ ID NO: 1847)  5′-ACCCUUUGUCUUCUUAAUGAUUGAA-3′ (SEQ ID NO: 1879)3′-UUUGGGAAACAGAAGAAUUACUAACUU-5′ (SEQ ID NO: 1817)AAT-1461 Target: 5′-AAACCCTTTGTCTTCTTAATGATTGAA-3′ (SEQ ID NO: 1848)  5′-CCCUUUGUCUUCUUAAUGAUUGAAC-3′ (SEQ ID NO: 1880)3′-UUGGGAAACAGAAGAAUUACUAACUUG-5′ (SEQ ID NO: 1818)AAT-1462 Target: 5′-AACCCTTTGTCTTCTTAATGATTGAAC-3′ (SEQ ID NO: 1849)  5′-CCUUUGUCUUCUUAAUGAUUGAACA-3′ (SEQ ID NO: 1881)3′-UGGGAAACAGAAGAAUUACUAACUUGU-5′ (SEQ ID NO: 1819)AAT-1463 Target: 5′-ACCCTTTGTCTTCTTAATGATTGAACA-3′ (SEQ ID NO: 1850)  5′-CUUUGUCUUCUUAAUGAUUGAACAA-3′ (SEQ ID NO: 1882)3′-GGGAAACAGAAGAAUUACUAACUUGUU-5′ (SEQ ID NO: 1820)AAT-1464 Target: 5′-CCCTTTGTCTTCTTAATGATTGAACAA-3′ (SEQ ID NO: 1851)  5′-UUUGUCUUCUUAAUGAUUGAACAAA-3′ (SEQ ID NO: 1883)3′-GGAAACAGAAGAAUUACUAACUUGUUU-5′ (SEQ ID NO: 1821)AAT-1465 Target: 5′-CCTTTGTCTTCTTAATGATTGAACAAA-3′ (SEQ ID NO: 1852)  5′-UUGUCUUCUUAAUGAUUGAACAAAA-3′ (SEQ ID NO: 1884)3′-GAAACAGAAGAAUUACUAACUUGUUUU-5′ (SEQ ID NO: 1822)AAT-1466 Target: 5′-CTTTGTCTTCTTAATGATTGAACAAAA-3′ (SEQ ID NO: 1853)  5′-UGUCUUCUUAAUGAUUGAACAAAAU-3′ (SEQ ID NO: 1885)3′-AAACAGAAGAAUUACUAACUUGUUUUA-5′ (SEQ ID NO: 1823)AAT-1467 Target: 5′-TTTGTCTTCTTAATGATTGAACAAAAT-3′ (SEQ ID NO: 1854)  5′-GUCUUCUUAAUGAUUGAACAAAAUA-3′ (SEQ ID NO: 1886)3′-AACAGAAGAAUUACUAACUUGUUUUAU-5′ (SEQ ID NO: 1824)AAT-1468 Target: 5′-TTGTCTTCTTAATGATTGAACAAAATA-3′ (SEQ ID NO: 1855)  5′-UCUUCUUAAUGAUUGAACAAAAUAC-3′ (SEQ ID NO: 1887)3′-ACAGAAGAAUUACUAACUUGUUUUAUG-5′ (SEQ ID NO: 1825)AAT-1469 Target: 5′-TGTCTTCTTAATGATTGAACAAAATAC-3′ (SEQ ID NO: 1856)  5′-CUUCUUAAUGAUUGAACAAAAUACC-3′ (SEQ ID NO: 1888)3′-CAGAAGAAUUACUAACUUGUUUUAUGG-5′ (SEQ ID NO: 1826)AAT-1470 Target: 5′-GTCTTCTTAATGATTGAACAAAATACC-3′ (SEQ ID NO: 1857)  5′-UUCUUAAUGAUUGAACAAAAUACCA-3′ (SEQ ID NO: 1889)3′-AGAAGAAUUACUAACUUGUUUUAUGGU-5′ (SEQ ID NO: 1827)AAT-1471 Target: 5′-TCTTCTTAATGATTGAACAAAATACCA-3′ (SEQ ID NO: 1858)  5′-UCUUAAUGAUUGAACAAAAUACCAA-3′ (SEQ ID NO: 1890)3′-GAAGAAUUACUAACUUGUUUUAUGGUU-5′ (SEQ ID NO: 1828)AAT-1472 Target: 5′-CTTCTTAATGATTGAACAAAATACCAA-3′ (SEQ ID NO: 1859)  5′-CUUAAUGAUUGAACAAAAUACCAAG-3′ (SEQ ID NO: 1891)3′-AAGAAUUACUAACUUGUUUUAUGGUUC-5′ (SEQ ID NO: 1829)AAT-1473 Target: 5′-TTCTTAATGATTGAACAAAATACCAAG-3′ (SEQ ID NO: 1860)  5′-UUAAUGAUUGAACAAAAUACCAAGU-3′ (SEQ ID NO: 1892)3′-AGAAUUACUAACUUGUUUUAUGGUUCA-5′ (SEQ ID NO: 1830)AAT-1474 Target: 5′-TCTTAATGATTGAACAAAATACCAAGT-3′ (SEQ ID NO: 1861)  5′-UAAUGAUUGAACAAAAUACCAAGUC-3′ (SEQ ID NO: 1893)3′-GAAUUACUAACUUGUUUUAUGGUUCAG-5′ (SEQ ID NO: 1831)AAT-1475 Target: 5′-CTTAATGATTGAACAAAATACCAAGTC-3′ (SEQ ID NO: 1862)  5′-AAUGAUUGAACAAAAUACCAAGUCU-3′ (SEQ ID NO: 1894)3′-AAUUACUAACUUGUUUUAUGGUUCAGA-5′ (SEQ ID NO: 1832)AAT-1476 Target: 5′-TTAATGATTGAACAAAATACCAAGTCT-3′ (SEQ ID NO: 1863)  5′-AUGAUUGAACAAAAUACCAAGUCUC-3′ (SEQ ID NO: 1895)3′-AUUACUAACUUGUUUUAUGGUUCAGAG-5′ (SEQ ID NO: 1833)AAT-1477 Target: 5′-TAATGATTGAACAAAATACCAAGTCTC-3′ (SEQ ID NO: 1864)  5′-UGAUUGAACAAAAUACCAAGUCUCC-3′ (SEQ ID NO: 1896)3′-UUACUAACUUGUUUUAUGGUUCAGAGG-5′ (SEQ ID NO: 1834)AAT-1478 Target: 5′-AATGATTGAACAAAATACCAAGTCTCC-3′ (SEQ ID NO: 1865)  5′-GAUUGAACAAAAUACCAAGUCUCCC-3′ (SEQ ID NO: 1897)3′-UACUAACUUGUUUUAUGGUUCAGAGGG-5′ (SEQ ID NO: 1835)AAT-1479 Target: 5′-ATGATTGAACAAAATACCAAGTCTCCC-3′ (SEQ ID NO: 1866)  5′-AUUGAACAAAAUACCAAGUCUCCCC-3′ (SEQ ID NO: 1898)3′-ACUAACUUGUUUUAUGGUUCAGAGGGG-5′ (SEQ ID NO: 1836)AAT-1480 Target: 5′-TGATTGAACAAAATACCAAGTCTCCCC-3′ (SEQ ID NO: 1867)  5′-UUGAACAAAAUACCAAGUCUCCCCU-3′ (SEQ ID NO: 1899)3′-CUAACUUGUUUUAUGGUUCAGAGGGGA-5′ (SEQ ID NO: 1837)AAT-1481 Target: 5′-GATTGAACAAAATACCAAGTCTCCCCT-3′ (SEQ ID NO: 1868)  5′-UGAACAAAAUACCAAGUCUCCCCUC-3′ (SEQ ID NO: 1900)3′-UAACUUGUUUUAUGGUUCAGAGGGGAG-5′ (SEQ ID NO: 1838)AAT-1482 Target: 5′-ATTGAACAAAATACCAAGTCTCCCCTC-3′ (SEQ ID NO: 1869)  5′-GAACAAAAUACCAAGUCUCCCCUCU-3′ (SEQ ID NO: 1901)3′-AACUUGUUUUAUGGUUCAGAGGGGAGA-5′ (SEQ ID NO: 1839)AAT-1483 Target: 5′-TTGAACAAAATACCAAGTCTCCCCTCT-3′ (SEQ ID NO: 1870)  5′-AACAAAAUACCAAGUCUCCCCUCUU-3′ (SEQ ID NO: 1902)3′-ACUUGUUUUAUGGUUCAGAGGGGAGAA-5′ (SEQ ID NO: 1840)AAT-1484 Target: 5′-TGAACAAAATACCAAGTCTCCCCTCTT-3′ (SEQ ID NO: 1871)  5′-ACAAAAUACCAAGUCUCCCCUCUUC-3′ (SEQ ID NO: 1903)3′-CUUGUUUUAUGGUUCAGAGGGGAGAAG-5′ (SEQ ID NO: 1841)AAT-1485 Target: 5′-GAACAAAATACCAAGTCTCCCCTCTTC-3′ (SEQ ID NO: 1872)  5′-CAAAAUACCAAGUCUCCCCUCUUCA-3′ (SEQ ID NO: 1904)3′-UUGUUUUAUGGUUCAGAGGGGAGAAGU-5′ (SEQ ID NO: 1842)AAT-1486 Target: 5′-AACAAAATACCAAGTCTCCCCTCTTCA-3′ (SEQ ID NO: 1873)  5′-AAAAUACCAAGUCUCCCCUCUUCAU-3′ (SEQ ID NO: 1905)3′-UGUUUUAUGGUUCAGAGGGGAGAAGUA-5′ (SEQ ID NO: 1843)AAT-1487 Target: 5′-ACAAAATACCAAGTCTCCCCTCTTCAT-3′ (SEQ ID NO: 1874)  5′-AAAUACCAAGUCUCCCCUCUUCAUG-3′ (SEQ ID NO: 1906)3′-GUUUUAUGGUUCAGAGGGGAGAAGUAC-5′ (SEQ ID NO: 1844)AAT-1488 Target: 5′-CAAAATACCAAGTCTCCCCTCTTCATG-3′ (SEQ ID NO: 1875)

TABLE 9Additional DsiRNA Target Sequences (21 mers) in α-1 antitrypsin mRNAAAT-1023 21 nt Target: 5′-AAGCGUUUAGGCAUGUUUAAC-3′ (SEQ ID NO: 1907)AAT-1024 21 nt Target: 5′-AGCGUUUAGGCAUGUUUAACA-3′ (SEQ ID NO: 1908)AAT-1404 21 nt Target: 5′-GGGGCCAUGUUUUUAGAGGCC-3′ (SEQ ID NO: 1909)AAT-1461 21 nt Target: 5′-AAACCCUUUGUCUUCUUAAUG-3′ (SEQ ID NO: 1910)AAT-1462 21 nt Target: 5′-AACCCUUUGUCUUCUUAAUGA-3′ (SEQ ID NO: 1911)AAT-1463 21 nt Target: 5′-ACCCUUUGUCUUCUUAAUGAU-3′ (SEQ ID NO: 1912)AAT-1464 21 nt Target: 5′-CCCUUUGUCUUCUUAAUGAUU-3′ (SEQ ID NO: 1913)AAT-1465 21 nt Target: 5′-CCUUUGUCUUCUUAAUGAUUG-3′ (SEQ ID NO: 1914)AAT-1466 21 nt Target: 5′-CUUUGUCUUCUUAAUGAUUGA-3′ (SEQ ID NO: 1915)AAT-1467 21 nt Target: 5′-UUUGUCUUCUUAAUGAUUGAA-3′ (SEQ ID NO: 1916)AAT-1468 21 nt Target: 5′-UUGUCUUCUUAAUGAUUGAAC-3′ (SEQ ID NO: 1917)AAT-1469 21 nt Target: 5′-UGUCUUCUUAAUGAUUGAACA-3′ (SEQ ID NO: 1918)AAT-1470 21 nt Target: 5′-GUCUUCUUAAUGAUUGAACAA-3′ (SEQ ID NO: 1919)AAT-1471 21 nt Target: 5′-UCUUCUUAAUGAUUGAACAAA-3′ (SEQ ID NO: 1920)AAT-1472 21 nt Target: 5′-CUUCUUAAUGAUUGAACAAAA-3′ (SEQ ID NO: 1921)AAT-1473 21 nt Target: 5′-UUCUUAAUGAUUGAACAAAAU-3′ (SEQ ID NO: 1922)AAT-1474 21 nt Target: 5′-UCUUAAUGAUUGAACAAAAUA-3′ (SEQ ID NO: 1923)AAT-1475 21 nt Target: 5′-CUUAAUGAUUGAACAAAAUAC-3′ (SEQ ID NO: 1924)AAT-1476 21 nt Target: 5′-UUAAUGAUUGAACAAAAUACC-3′ (SEQ ID NO: 1925)AAT-1477 21 nt Target: 5′-UAAUGAUUGAACAAAAUACCA-3′ (SEQ ID NO: 1926)AAT-1478 21 nt Target: 5′-AAUGAUUGAACAAAAUACCAA-3′ (SEQ ID NO: 1927)AAT-1479 21 nt Target: 5′-AUGAUUGAACAAAAUACCAAG-3′ (SEQ ID NO: 1928)AAT-1480 21 nt Target: 5′-UGAUUGAACAAAAUACCAAGU-3′ (SEQ ID NO: 1929)AAT-1481 21 nt Target: 5′-GAUUGAACAAAAUACCAAGUC-3′ (SEQ ID NO: 1930)AAT-1482 21 nt Target: 5′-AUUGAACAAAAUACCAAGUCU-3′ (SEQ ID NO: 1931)AAT-1483 21 nt Target: 5′-UUGAACAAAAUACCAAGUCUC-3′ (SEQ ID NO: 1932)AAT-1484 21 nt Target: 5′-UGAACAAAAUACCAAGUCUCC-3′ (SEQ ID NO: 1933)AAT-1485 21 nt Target: 5′-GAACAAAAUACCAAGUCUCCC-3′ (SEQ ID NO: 1934)AAT-1486 21 nt Target: 5′-AACAAAAUACCAAGUCUCCCC-3′ (SEQ ID NO: 1935)AAT-1487 21 nt Target: 5′-ACAAAAUACCAAGUCUCCCCU-3′ (SEQ ID NO: 1936)AAT-1488 21 nt Target: 5′-CAAAAUACCAAGUCUCCCCUC-3′ (SEQ ID NO: 1937)

TABLE 10 Additional Human Anti-α-1 antitrypsin “Blunt/Blunt” DsiRNAs5′-AAGCGUUUAGGCAUGUUUAACAUCCAG-3′ (SEQ ID NO: 1938)3′-UUCGCAAAUCCGUACAAAUUGUAGGUC-5′ (SEQ ID NO: 1814)AAT-1023 Target: 5′-AAGCGTTTAGGCATGTTTAACATCCAG-3′ (SEQ ID NO: 1845)5′-AGCGUUUAGGCAUGUUUAACAUCCAGC-3′ (SEQ ID NO: 1939)3′-UCGCAAAUCCGUACAAAUUGUAGGUCG-5′ (SEQ ID NO: 1815)AAT-1024 Target: 5′-AGCGTTTAGGCATGTTTAACATCCAGC-3′ (SEQ ID NO: 1846)5′-GGGGCCAUGUUUUUAGAGGCCAUACCC-3′ (SEQ ID NO: 1940)3′-CCCCGGUACAAAAAUCUCCGGUAUGGG-5′ (SEQ ID NO: 1816)AAT-1404 Target: 5′-GGGGCCATGTTTTTAGAGGCCATACCC-3′ (SEQ ID NO: 1847)5′-AAACCCUUUGUCUUCUUAAUGAUUGAA-3′ (SEQ ID NO: 1941)3′-UUUGGGAAACAGAAGAAUUACUAACUU-5′ (SEQ ID NO: 1817)AAT-1461 Target: 5′-AAACCCTTTGTCTTCTTAATGATTGAA-3′ (SEQ ID NO: 1848)5′-AACCCUUUGUCUUCUUAAUGAUUGAAC-3′ (SEQ ID NO: 1942)3′-UUGGGAAACAGAAGAAUUACUAACUUG-5′ (SEQ ID NO: 1818)AAT-1462 Target: 5′-AACCCTTTGTCTTCTTAATGATTGAAC-3′ (SEQ ID NO: 1849)5′-ACCCUUUGUCUUCUUAAUGAUUGAACA-3′ (SEQ ID NO: 1943)3′-UGGGAAACAGAAGAAUUACUAACUUGU-5′ (SEQ ID NO: 1819)AAT-1463 Target: 5′-ACCCTTTGTCTTCTTAATGATTGAACA-3′ (SEQ ID NO: 1850)5′-CCCUUUGUCUUCUUAAUGAUUGAACAA-3′ (SEQ ID NO: 1944)3′-GGGAAACAGAAGAAUUACUAACUUGUU-5′ (SEQ ID NO: 1820)AAT-1464 Target: 5′-CCCTTTGTCTTCTTAATGATTGAACAA-3′ (SEQ ID NO: 1851)5′-CCUUUGUCUUCUUAAUGAUUGAACAAA-3′ (SEQ ID NO: 1945)3′-GGAAACAGAAGAAUUACUAACUUGUUU-5′ (SEQ ID NO: 1821)AAT-1465 Target: 5′-CCTTTGTCTTCTTAATGATTGAACAAA-3′ (SEQ ID NO: 1852)5′-CUUUGUCUUCUUAAUGAUUGAACAAAA-3′ (SEQ ID NO: 1946)3′-GAAACAGAAGAAUUACUAACUUGUUUU-5′ (SEQ ID NO: 1822)AAT-1466 Target: 5′-CTTTGTCTTCTTAATGATTGAACAAAA-3′ (SEQ ID NO: 1853)5′-UUUGUCUUCUUAAUGAUUGAACAAAAU-3′ (SEQ ID NO: 1947)3′-AAACAGAAGAAUUACUAACUUGUUUUA-5′ (SEQ ID NO: 1823)AAT-1467 Target: 5′-TTTGTCTTCTTAATGATTGAACAAAAT-3′ (SEQ ID NO: 1854)5′-UUGUCUUCUUAAUGAUUGAACAAAAUA-3′ (SEQ ID NO: 1948)3′-AACAGAAGAAUUACUAACUUGUUUUAU-5′ (SEQ ID NO: 1824)AAT-1468 Target: 5′-TTGTCTTCTTAATGATTGAACAAAATA-3′ (SEQ ID NO: 1855)5′-UGUCUUCUUAAUGAUUGAACAAAAUAC-3′ (SEQ ID NO: 1949)3′-ACAGAAGAAUUACUAACUUGUUUUAUG-5′ (SEQ ID NO: 1825)AAT-1469 Target: 5′-TGTCTTCTTAATGATTGAACAAAATAC-3′ (SEQ ID NO: 1856)5′-GUCUUCUUAAUGAUUGAACAAAAUACC-3′ (SEQ ID NO: 1950)3′-CAGAAGAAUUACUAACUUGUUUUAUGG-5′ (SEQ ID NO: 1826)AAT-1470 Target: 5′-GTCTTCTTAATGATTGAACAAAATACC-3′ (SEQ ID NO: 1857)5′-UCUUCUUAAUGAUUGAACAAAAUACCA-3′ (SEQ ID NO: 1951)3′-AGAAGAAUUACUAACUUGUUUUAUGGU-5′ (SEQ ID NO: 1827)AAT-1471 Target: 5′-TCTTCTTAATGATTGAACAAAATACCA-3′ (SEQ ID NO: 1858)5′-CUUCUUAAUGAUUGAACAAAAUACCAA-3′ (SEQ ID NO: 1952)3′-GAAGAAUUACUAACUUGUUUUAUGGUU-5′ (SEQ ID NO: 1828)AAT-1472 Target: 5′-CTTCTTAATGATTGAACAAAATACCAA-3′ (SEQ ID NO: 1859)5′-UUCUUAAUGAUUGAACAAAAUACCAAG-3′ (SEQ ID NO: 1953)3′-AAGAAUUACUAACUUGUUUUAUGGUUC-5′ (SEQ ID NO: 1829)AAT-1473 Target: 5′-TTCTTAATGATTGAACAAAATACCAAG-3′ (SEQ ID NO: 1860)5′-UCUUAAUGAUUGAACAAAAUACCAAGU-3′ (SEQ ID NO: 1954)3′-AGAAUUACUAACUUGUUUUAUGGUUCA-5′ (SEQ ID NO: 1830)AAT-1474 Target: 5′-TCTTAATGATTGAACAAAATACCAAGT-3′ (SEQ ID NO: 1861)5′-CUUAAUGAUUGAACAAAAUACCAAGUC-3′ (SEQ ID NO: 1955)3′-GAAUUACUAACUUGUUUUAUGGUUCAG-5′ (SEQ ID NO: 1831)AAT-1475 Target: 5′-CTTAATGATTGAACAAAATACCAAGTC-3′ (SEQ ID NO: 1862)5′-UUAAUGAUUGAACAAAAUACCAAGUCU-3′ (SEQ ID NO: 1956)3′-AAUUACUAACUUGUUUUAUGGUUCAGA-5′ (SEQ ID NO: 1832)AAT-1476 Target: 5′-TTAATGATTGAACAAAATACCAAGTCT-3′ (SEQ ID NO: 1863)5′-UAAUGAUUGAACAAAAUACCAAGUCUC-3′ (SEQ ID NO: 1957)3′-AUUACUAACUUGUUUUAUGGUUCAGAG-5′ (SEQ ID NO: 1833)AAT-1477 Target: 5′-TAATGATTGAACAAAATACCAAGTCTC-3′ (SEQ ID NO: 1864)5′-AAUGAUUGAACAAAAUACCAAGUCUCC-3′ (SEQ ID NO: 1958)3′-UUACUAACUUGUUUUAUGGUUCAGAGG-5′ (SEQ ID NO: 1834)AAT-1478 Target: 5′-AATGATTGAACAAAATACCAAGTCTCC-3′ (SEQ ID NO: 1865)5′-AUGAUUGAACAAAAUACCAAGUCUCCC-3′ (SEQ ID NO: 1959)3′-UACUAACUUGUUUUAUGGUUCAGAGGG-5′ (SEQ ID NO: 1835)AAT-1479 Target: 5′-ATGATTGAACAAAATACCAAGTCTCCC-3′ (SEQ ID NO: 1866)5′-UGAUUGAACAAAAUACCAAGUCUCCCC-3′ (SEQ ID NO: 1960)3′-ACUAACUUGUUUUAUGGUUCAGAGGGG-5′ (SEQ ID NO: 1836)AAT-1480 Target: 5′-TGATTGAACAAAATACCAAGTCTCCCC-3′ (SEQ ID NO: 1867)5′-GAUUGAACAAAAUACCAAGUCUCCCCU-3′ (SEQ ID NO: 1961)3′-CUAACUUGUUUUAUGGUUCAGAGGGGA-5′ (SEQ ID NO: 1837)AAT-1481 Target: 5′-GATTGAACAAAATACCAAGTCTCCCCT-3′ (SEQ ID NO: 1868)5′-AUUGAACAAAAUACCAAGUCUCCCCUC-3′ (SEQ ID NO: 1962)3′-UAACUUGUUUUAUGGUUCAGAGGGGAG-5′ (SEQ ID NO: 1838)AAT-1482 Target: 5′-ATTGAACAAAATACCAAGTCTCCCCTC-3′ (SEQ ID NO: 1869)5′-UUGAACAAAAUACCAAGUCUCCCCUCU-3′ (SEQ ID NO: 1963)3′-AACUUGUUUUAUGGUUCAGAGGGGAGA-5′ (SEQ ID NO: 1839)AAT-1483 Target: 5′-TTGAACAAAATACCAAGTCTCCCCTCT-3′ (SEQ ID NO: 1870)5′-UGAACAAAAUACCAAGUCUCCCCUCUU-3′ (SEQ ID NO: 1964)3′-ACUUGUUUUAUGGUUCAGAGGGGAGAA-5′ (SEQ ID NO: 1840)AAT-1484 Target: 5′-TGAACAAAATACCAAGTCTCCCCTCTT-3′ (SEQ ID NO: 1871)5′-GAACAAAAUACCAAGUCUCCCCUCUUC-3′ (SEQ ID NO: 1965)3′-CUUGUUUUAUGGUUCAGAGGGGAGAAG-5′ (SEQ ID NO: 1841)AAT-1485 Target: 5′-GAACAAAATACCAAGTCTCCCCTCTTC-3′ (SEQ ID NO: 1872)5′-AACAAAAUACCAAGUCUCCCCUCUUCA-3′ (SEQ ID NO: 1966)3′-UUGUUUUAUGGUUCAGAGGGGAGAAGU-5′ (SEQ ID NO: 1842)AAT-1486 Target: 5′-AACAAAATACCAAGTCTCCCCTCTTCA-3′ (SEQ ID NO: 1873)5′-ACAAAAUACCAAGUCUCCCCUCUUCAU-3′ (SEQ ID NO: 1967)3′-UGUUUUAUGGUUCAGAGGGGAGAAGUA-5′ (SEQ ID NO: 1843)AAT-1487 Target: 5′-ACAAAATACCAAGTCTCCCCTCTTCAT-3′ (SEQ ID NO: 1874)5′-CAAAAUACCAAGUCUCCCCUCUUCAUG-3′ (SEQ ID NO: 1968)3′-GUUUUAUGGUUCAGAGGGGAGAAGUAC-5′ (SEQ ID NO: 1844)AAT-1488 Target: 5′-CAAAATACCAAGTCTCCCCTCTTCATG-3′ (SEQ ID NO: 1875)

TABLE 11Additional DsiRNA Component 19 Nucleotide Target Sequences in α-1antitrypsin mRNAAAT-1023 19 nt Target #1: 5′-GCGUUUAGGCAUGUUUAAC-3′ (SEQ ID NO: 1969)AAT-1023 19 nt Target #2: 5′-AGCGUUUAGGCAUGUUUAA-3′ (SEQ ID NO: 2000)AAT-1023 19 nt Target #3: 5′-AAGCGUUUAGGCAUGUUUA-3′ (SEQ ID NO: 2031)AAT-1024 19 nt Target #1: 5′-CGUUUAGGCAUGUUUAACA-3′ (SEQ ID NO: 1970)AAT-1024 19 nt Target #2: 5′-GCGUUUAGGCAUGUUUAAC-3′ (SEQ ID NO: 2001)AAT-1024 19 nt Target #3: 5′-AGCGUUUAGGCAUGUUUAA-3′ (SEQ ID NO: 2032)AAT-1404 19 nt Target #1: 5′-GGCCAUGUUUUUAGAGGCC-3′ (SEQ ID NO: 1971)AAT-1404 19 nt Target #2: 5′-GGGCCAUGUUUUUAGAGGC-3′ (SEQ ID NO: 2002)AAT-1404 19 nt Target #3: 5′-GGGGCCAUGUUUUUAGAGG-3′ (SEQ ID NO: 2033)AAT-1461 19 nt Target #1: 5′-ACCCUUUGUCUUCUUAAUG-3′ (SEQ ID NO: 1972)AAT-1461 19 nt Target #2: 5′-AACCCUUUGUCUUCUUAAU-3′ (SEQ ID NO: 2003)AAT-1461 19 nt Target #3: 5′-AAACCCUUUGUCUUCUUAA-3′ (SEQ ID NO: 2034)AAT-1462 19 nt Target #1: 5′-CCCUUUGUCUUCUUAAUGA-3′ (SEQ ID NO: 1973)AAT-1462 19 nt Target #2: 5′-ACCCUUUGUCUUCUUAAUG-3′ (SEQ ID NO: 2004)AAT-1462 19 nt Target #3: 5′-AACCCUUUGUCUUCUUAAU-3′ (SEQ ID NO: 2035)AAT-1463 19 nt Target #1: 5′-CCUUUGUCUUCUUAAUGAU-3′ (SEQ ID NO: 1974)AAT-1463 19 nt Target #2: 5′-CCCUUUGUCUUCUUAAUGA-3′ (SEQ ID NO: 2005)AAT-1463 19 nt Target #3: 5′-ACCCUUUGUCUUCUUAAUG-3′ (SEQ ID NO: 2036)AAT-1464 19 nt Target #1: 5′-CUUUGUCUUCUUAAUGAUU-3′ (SEQ ID NO: 1975)AAT-1464 19 nt Target #2: 5′-CCUUUGUCUUCUUAAUGAU-3′ (SEQ ID NO: 2006)AAT-1464 19 nt Target #3: 5′-CCCUUUGUCUUCUUAAUGA-3′ (SEQ ID NO: 2037)AAT-1465 19 nt Target #1: 5′-UUUGUCUUCUUAAUGAUUG-3′ (SEQ ID NO: 1976)AAT-1465 19 nt Target #2: 5′-CUUUGUCUUCUUAAUGAUU-3′ (SEQ ID NO: 2007)AAT-1465 19 nt Target #3: 5′-CCUUUGUCUUCUUAAUGAU-3′ (SEQ ID NO: 2038)AAT-1466 19 nt Target #1: 5′-UUGUCUUCUUAAUGAUUGA-3′ (SEQ ID NO: 1977)AAT-1466 19 nt Target #2: 5′-UUUGUCUUCUUAAUGAUUG-3′ (SEQ ID NO: 2008)AAT-1466 19 nt Target #3: 5′-CUUUGUCUUCUUAAUGAUU-3′ (SEQ ID NO: 2039)AAT-1467 19 nt Target #1: 5′-UGUCUUCUUAAUGAUUGAA-3′ (SEQ ID NO: 1978)AAT-1467 19 nt Target #2: 5′-UUGUCUUCUUAAUGAUUGA-3′ (SEQ ID NO: 2009)AAT-1467 19 nt Target #3: 5′-UUUGUCUUCUUAAUGAUUG-3′ (SEQ ID NO: 2040)AAT-1468 19 nt Target #1: 5′-GUCUUCUUAAUGAUUGAAC-3′ (SEQ ID NO: 1979)AAT-1468 19 nt Target #2: 5′-UGUCUUCUUAAUGAUUGAA-3′ (SEQ ID NO: 2010)AAT-1468 19 nt Target #3: 5′-UUGUCUUCUUAAUGAUUGA-3′ (SEQ ID NO: 2041)AAT-1469 19 nt Target #1: 5′-UCUUCUUAAUGAUUGAACA-3′ (SEQ ID NO: 1980)AAT-1469 19 nt Target #2: 5′-GUCUUCUUAAUGAUUGAAC-3′ (SEQ ID NO: 2011)AAT-1469 19 nt Target #3: 5′-UGUCUUCUUAAUGAUUGAA-3′ (SEQ ID NO: 2042)AAT-1470 19 nt Target #1: 5′-CUUCUUAAUGAUUGAACAA-3′ (SEQ ID NO: 1981)AAT-1470 19 nt Target #2: 5′-UCUUCUUAAUGAUUGAACA-3′ (SEQ ID NO: 2012)AAT-1470 19 nt Target #3: 5′-GUCUUCUUAAUGAUUGAAC-3′ (SEQ ID NO: 2043)AAT-1471 19 nt Target #1: 5′-UUCUUAAUGAUUGAACAAA-3′ (SEQ ID NO: 1982)AAT-1471 19 nt Target #2: 5′-CUUCUUAAUGAUUGAACAA-3′ (SEQ ID NO: 2013)AAT-1471 19 nt Target #3: 5′-UCUUCUUAAUGAUUGAACA-3′ (SEQ ID NO: 2044)AAT-1472 19 nt Target #1: 5′-UCUUAAUGAUUGAACAAAA-3′ (SEQ ID NO: 1983)AAT-1472 19 nt Target #2: 5′-UUCUUAAUGAUUGAACAAA-3′ (SEQ ID NO: 2014)AAT-1472 19 nt Target #3: 5′-CUUCUUAAUGAUUGAACAA-3′ (SEQ ID NO: 2045)AAT-1473 19 nt Target #1: 5′-CUUAAUGAUUGAACAAAAU-3′ (SEQ ID NO: 1984)AAT-1473 19 nt Target #2: 5′-UCUUAAUGAUUGAACAAAA-3′ (SEQ ID NO: 2015)AAT-1473 19 nt Target #3: 5′-UUCUUAAUGAUUGAACAAA-3′ (SEQ ID NO: 2046)AAT-1474 19 nt Target #1: 5′-UUAAUGAUUGAACAAAAUA-3′ (SEQ ID NO: 1985)AAT-1474 19 nt Target #2: 5′-CUUAAUGAUUGAACAAAAU-3′ (SEQ ID NO: 2016)AAT-1474 19 nt Target #3: 5′-UCUUAAUGAUUGAACAAAA-3′ (SEQ ID NO: 2047)AAT-1475 19 nt Target #1: 5′-UAAUGAUUGAACAAAAUAC-3′ (SEQ ID NO: 1986)AAT-1475 19 nt Target #2: 5′-UUAAUGAUUGAACAAAAUA-3′ (SEQ ID NO: 2017)AAT-1475 19 nt Target #3: 5′-CUUAAUGAUUGAACAAAAU-3′ (SEQ ID NO: 2048)AAT-1476 19 nt Target #1: 5′-AAUGAUUGAACAAAAUACC-3′ (SEQ ID NO: 1987)AAT-1476 19 nt Target #2: 5′-UAAUGAUUGAACAAAAUAC-3′ (SEQ ID NO: 2018)AAT-1476 19 nt Target #3: 5′-UUAAUGAUUGAACAAAAUA-3′ (SEQ ID NO: 2049)AAT-1477 19 nt Target #1: 5′-AUGAUUGAACAAAAUACCA-3′ (SEQ ID NO: 1988)AAT-1477 19 nt Target #2: 5′-AAUGAUUGAACAAAAUACC-3′ (SEQ ID NO: 2019)AAT-1477 19 nt Target #3: 5′-UAAUGAUUGAACAAAAUAC-3′ (SEQ ID NO: 2050)AAT-1478 19 nt Target #1: 5′-UGAUUGAACAAAAUACCAA-3′ (SEQ ID NO: 1989)AAT-1478 19 nt Target #2: 5′-AUGAUUGAACAAAAUACCA-3′ (SEQ ID NO: 2020)AAT-1478 19 nt Target #3: 5′-AAUGAUUGAACAAAAUACC-3′ (SEQ ID NO: 2051)AAT-1479 19 nt Target #1: 5′-GAUUGAACAAAAUACCAAG-3′ (SEQ ID NO: 1990)AAT-1479 19 nt Target #2: 5′-UGAUUGAACAAAAUACCAA-3′ (SEQ ID NO: 2021)AAT-1479 19 nt Target #3: 5′-AUGAUUGAACAAAAUACCA-3′ (SEQ ID NO: 2052)AAT-1480 19 nt Target #1: 5′-AUUGAACAAAAUACCAAGU-3′ (SEQ ID NO: 1991)AAT-1480 19 nt Target #2: 5′-GAUUGAACAAAAUACCAAG-3′ (SEQ ID NO: 2022)AAT-1480 19 nt Target #3: 5′-UGAUUGAACAAAAUACCAA-3′ (SEQ ID NO: 2053)AAT-1481 19 nt Target #1: 5′-UUGAACAAAAUACCAAGUC-3′ (SEQ ID NO: 1992)AAT-1481 19 nt Target #2: 5′-AUUGAACAAAAUACCAAGU-3′ (SEQ ID NO: 2023)AAT-1481 19 nt Target #3: 5′-GAUUGAACAAAAUACCAAG-3′ (SEQ ID NO: 2054)AAT-1482 19 nt Target #1: 5′-UGAACAAAAUACCAAGUCU-3′ (SEQ ID NO: 1993)AAT-1482 19 nt Target #2: 5′-UUGAACAAAAUACCAAGUC-3′ (SEQ ID NO: 2024)AAT-1482 19 nt Target #3: 5′-AUUGAACAAAAUACCAAGU-3′ (SEQ ID NO: 2055)AAT-1483 19 nt Target #1: 5′-GAACAAAAUACCAAGUCUC-3′ (SEQ ID NO: 1994)AAT-1483 19 nt Target #2: 5′-UGAACAAAAUACCAAGUCU-3′ (SEQ ID NO: 2025)AAT-1483 19 nt Target #3: 5′-UUGAACAAAAUACCAAGUC-3′ (SEQ ID NO: 2056)AAT-1484 19 nt Target #1: 5′-AACAAAAUACCAAGUCUCC-3′ (SEQ ID NO: 1995)AAT-1484 19 nt Target #2: 5′-GAACAAAAUACCAAGUCUC-3′ (SEQ ID NO: 2026)AAT-1484 19 nt Target #3: 5′-UGAACAAAAUACCAAGUCU-3′ (SEQ ID NO: 2057)AAT-1485 19 nt Target #1: 5′-ACAAAAUACCAAGUCUCCC-3′ (SEQ ID NO: 1996)AAT-1485 19 nt Target #2: 5′-AACAAAAUACCAAGUCUCC-3′ (SEQ ID NO: 2027)AAT-1485 19 nt Target #3: 5′-GAACAAAAUACCAAGUCUC-3′ (SEQ ID NO: 2058)AAT-1486 19 nt Target #1: 5′-CAAAAUACCAAGUCUCCCC-3′ (SEQ ID NO: 1997)AAT-1486 19 nt Target #2: 5′-ACAAAAUACCAAGUCUCCC-3′ (SEQ ID NO: 2028)AAT-1486 19 nt Target #3: 5′-AACAAAAUACCAAGUCUCC-3′ (SEQ ID NO: 2059)AAT-1487 19 nt Target #1: 5′-AAAAUACCAAGUCUCCCCU-3′ (SEQ ID NO: 1998)AAT-1487 19 nt Target #2: 5′-CAAAAUACCAAGUCUCCCC-3′ (SEQ ID NO: 2029)AAT-1487 19 nt Target #3: 5′-ACAAAAUACCAAGUCUCCC-3′ (SEQ ID NO: 2060)AAT-1488 19 nt Target #1: 5′-AAAUACCAAGUCUCCCCUC-3′ (SEQ ID NO: 1999)AAT-1488 19 nt Target #2: 5′-AAAAUACCAAGUCUCCCCU-3′ (SEQ ID NO: 2030)AAT-1488 19 nt Target #3: 5′-CAAAAUACCAAGUCUCCCC-3′ (SEQ ID NO: 2061)

TABLE 12 Further Human Anti-α-1 antitrypsin DsiRNA Agents (Asymmetries)  5′-CCAGGGAGAUGCUGCCCAGAAGAca-3′ (SEQ ID NO: 2062)3′-GGGGUCCCUCUACGACGGGUCUUCUGU-5′ (SEQ ID NO: 2202)AAT-366 Target: 5′-CCCCAGGGAGATGCTGCCCAGAAGACA-3′ (SEQ ID NO: 2342)  5′-CAGGGAGAUGCUGCCCAGAAGACag-3′ (SEQ ID NO: 2063)3′-GGGUCCCUCUACGACGGGUCUUCUGUC-5′ (SEQ ID NO: 2203)AAT-367 Target: 5′-CCCAGGGAGATGCTGCCCAGAAGACAG-3′ (SEQ ID NO: 2343)  5′-AGGGAGAUGCUGCCCAGAAGACAga-3′ (SEQ ID NO: 2064)3′-GGUCCCUCUACGACGGGUCUUCUGUCU-5′ (SEQ ID NO: 2204)AAT-368 Target: 5′-CCAGGGAGATGCTGCCCAGAAGACAGA-3′ (SEQ ID NO: 2344)  5′-GGGAGAUGCUGCCCAGAAGACAGat-3′ (SEQ ID NO: 2065)3′-GUCCCUCUACGACGGGUCUUCUGUCUA-5′ (SEQ ID NO: 2205)AAT-369 Target: 5′-CAGGGAGATGCTGCCCAGAAGACAGAT-3′ (SEQ ID NO: 2345)  5′-GGAGAUGCUGCCCAGAAGACAGAta-3′ (SEQ ID NO: 2066)3′-UCCCUCUACGACGGGUCUUCUGUCUAU-5′ (SEQ ID NO: 2206)AAT-370 Target: 5′-AGGGAGATGCTGCCCAGAAGACAGATA-3′ (SEQ ID NO: 2346)  5′-GAGAUGCUGCCCAGAAGACAGAUac-3′ (SEQ ID NO: 2067)3′-CCCUCUACGACGGGUCUUCUGUCUAUG-5′ (SEQ ID NO: 2207)AAT-371 Target: 5′-GGGAGATGCTGCCCAGAAGACAGATAC-3′ (SEQ ID NO: 2347)  5′-GAUACAUCCCACCAUGAUCAGGAtc-3′ (SEQ ID NO: 2068)3′-GUCUAUGUAGGGUGGUACUAGUCCUAG-5′ (SEQ ID NO: 2208)AAT-391 Target: 5′-CAGATACATCCCACCATGATCAGGATC-3′ (SEQ ID NO: 2348)  5′-AUACAUCCCACCAUGAUCAGGAUca-3′ (SEQ ID NO: 2069)3′-UCUAUGUAGGGUGGUACUAGUCCUAGU-5′ (SEQ ID NO: 2209)AAT-392 Target: 5′-AGATACATCCCACCATGATCAGGATCA-3′ (SEQ ID NO: 2349)  5′-UACAUCCCACCAUGAUCAGGAUCac-3′ (SEQ ID NO: 2070)3′-CUAUGUAGGGUGGUACUAGUCCUAGUG-5′ (SEQ ID NO: 2210)AAT-393 Target: 5′-GATACATCCCACCATGATCAGGATCAC-3′ (SEQ ID NO: 2350)  5′-ACAUCCCACCAUGAUCAGGAUCACC-3′ (SEQ ID NO: 2071)3′-UAUGUAGGGUGGUACUAGUCCUAGUGG-5′ (SEQ ID NO: 2211)AAT-394 Target: 5′-ATACATCCCACCATGATCAGGATCACC-3′ (SEQ ID NO: 2351)  5′-ACCAGUCCAACAGCACCAAUAUCtt-3′ (SEQ ID NO: 2072)3′-UGUGGUCAGGUUGUCGUGGUUAUAGAA-5′ (SEQ ID NO: 2212)AAT-485 Target: 5′-ACACCAGTCCAACAGCACCAATATCTT-3′ (SEQ ID NO: 2352)  5′-CCAGUCCAACAGCACCAAUAUCUtc-3′ (SEQ ID NO: 2073)3′-GUGGUCAGGUUGUCGUGGUUAUAGAAG-5′ (SEQ ID NO: 2213)AAT-486 Target: 5′-CACCAGTCCAACAGCACCAATATCTTC-3′ (SEQ ID NO: 2353)  5′-CAGUCCAACAGCACCAAUAUCUUct-3′ (SEQ ID NO: 2074)3′-UGGUCAGGUUGUCGUGGUUAUAGAAGA-5′ (SEQ ID NO: 2214)AAT-487 Target: 5′-ACCAGTCCAACAGCACCAATATCTTCT-3′ (SEQ ID NO: 2354)  5′-AGUCCAACAGCACCAAUAUCUUCtt-3′ (SEQ ID NO: 2075)3′-GGUCAGGUUGUCGUGGUUAUAGAAGAA-5′ (SEQ ID NO: 2215)AAT-488 Target: 5′-CCAGTCCAACAGCACCAATATCTTCTT-3′ (SEQ ID NO: 2355)  5′-GUCCAACAGCACCAAUAUCUUCUtc-3′ (SEQ ID NO: 2076)3′-GUCAGGUUGUCGUGGUUAUAGAAGAAG-5′ (SEQ ID NO: 2216)AAT-489 Target: 5′-CAGTCCAACAGCACCAATATCTTCTTC-3′ (SEQ ID NO: 2356)  5′-UCCAACAGCACCAAUAUCUUCUUct-3′ (SEQ ID NO: 2077)3′-UCAGGUUGUCGUGGUUAUAGAAGAAGA-5′ (SEQ ID NO: 2217)AAT-490 Target: 5′-AGTCCAACAGCACCAATATCTTCTTCT-3′ (SEQ ID NO: 2357)  5′-CCAACAGCACCAAUAUCUUCUUCtc-3′ (SEQ ID NO: 2078)3′-CAGGUUGUCGUGGUUAUAGAAGAAGAG-5′ (SEQ ID NO: 2218)AAT-491 Target: 5′-GTCCAACAGCACCAATATCTTCTTCTC-3′ (SEQ ID NO: 2358)  5′-CAACAGCACCAAUAUCUUCUUCUcC-3′ (SEQ ID NO: 2079)3′-AGGUUGUCGUGGUUAUAGAAGAAGAGG-5′ (SEQ ID NO: 2219)AAT-492 Target: 5′-TCCAACAGCACCAATATCTTCTTCTCC-3′ (SEQ ID NO: 2359)  5′-AACAGCACCAAUAUCUUCUUCUCCC-3′ (SEQ ID NO: 2080)3′-GGUUGUCGUGGUUAUAGAAGAAGAGGG-5′ (SEQ ID NO: 2220)AAT-493 Target: 5′-CCAACAGCACCAATATCTTCTTCTCCC-3′ (SEQ ID NO: 2360)  5′-ACAGCACCAAUAUCUUCUUCUCCCC-3′ (SEQ ID NO: 2081)3′-GUUGUCGUGGUUAUAGAAGAAGAGGGG-5′ (SEQ ID NO: 2221)AAT-494 Target: 5′-CAACAGCACCAATATCTTCTTCTCCCC-3′ (SEQ ID NO: 2361)  5′-CAGCACCAAUAUCUUCUUCUCCCca-3′ (SEQ ID NO: 2082)3′-UUGUCGUGGUUAUAGAAGAAGAGGGGU-5′ (SEQ ID NO: 2222)AAT-495 Target: 5′-AACAGCACCAATATCTTCTTCTCCCCA-3′ (SEQ ID NO: 2362)  5′-AGCACCAAUAUCUUCUUCUCCCCag-3′ (SEQ ID NO: 2083)3′-UGUCGUGGUUAUAGAAGAAGAGGGGUC-5′ (SEQ ID NO: 2223)AAT-496 Target: 5′-ACAGCACCAATATCTTCTTCTCCCCAG-3′ (SEQ ID NO: 2363)  5′-GCACCAAUAUCUUCUUCUCCCCAgt-3′ (SEQ ID NO: 2084)3′-GUCGUGGUUAUAGAAGAAGAGGGGUCA-5′ (SEQ ID NO: 2224)AAT-497 Target: 5′-CAGCACCAATATCTTCTTCTCCCCAGT-3′ (SEQ ID NO: 2364)  5′-CACCAAUAUCUUCUUCUCCCCAGtg-3′ (SEQ ID NO: 2085)3′-UCGUGGUUAUAGAAGAAGAGGGGUCAC-5′ (SEQ ID NO: 2225)AAT-498 Target: 5′-AGCACCAATATCTTCTTCTCCCCAGTG-3′ (SEQ ID NO: 2365)  5′-ACCAAUAUCUUCUUCUCCCCAGUga-3′ (SEQ ID NO: 2086)3′-CGUGGUUAUAGAAGAAGAGGGGUCACU-5′ (SEQ ID NO: 2226)AAT-499 Target: 5′-GCACCAATATCTTCTTCTCCCCAGTGA-3′ (SEQ ID NO: 2366)  5′-CCCAGUGAGCAUCGCUACAGCCUtt-3′ (SEQ ID NO: 2087)3′-AGGGGUCACUCGUAGCGAUGUCGGAAA-5′ (SEQ ID NO: 2227)AAT-516 Target: 5′-TCCCCAGTGAGCATCGCTACAGCCTTT-3′ (SEQ ID NO: 2367)  5′-CCAGUGAGCAUCGCUACAGCCUUtg-3′ (SEQ ID NO: 2088)3′-GGGGUCACUCGUAGCGAUGUCGGAAAC-5′ (SEQ ID NO: 2228)AAT-517 Target: 5′-CCCCAGTGAGCATCGCTACAGCCTTTG-3′ (SEQ ID NO: 2368)  5′-CAGUGAGCAUCGCUACAGCCUUUgc-3′ (SEQ ID NO: 2089)3′-GGGUCACUCGUAGCGAUGUCGGAAACG-5′ (SEQ ID NO: 2229)AAT-518 Target: 5′-CCCAGTGAGCATCGCTACAGCCTTTGC-3′ (SEQ ID NO: 2369)  5′-AGUGAGCAUCGCUACAGCCUUUGca-3′ (SEQ ID NO: 2090)3′-GGUCACUCGUAGCGAUGUCGGAAACGU-5′ (SEQ ID NO: 2230)AAT-519 Target: 5′-CCAGTGAGCATCGCTACAGCCTTTGCA-3′ (SEQ ID NO: 2370)  5′-GUGAGCAUCGCUACAGCCUUUGCaa-3′ (SEQ ID NO: 2091)3′-GUCACUCGUAGCGAUGUCGGAAACGUU-5′ (SEQ ID NO: 2231)AAT-520 Target: 5′-CAGTGAGCATCGCTACAGCCTTTGCAA-3′ (SEQ ID NO: 2371)  5′-UGAGCAUCGCUACAGCCUUUGCAat-3′ (SEQ ID NO: 2092)3′-UCACUCGUAGCGAUGUCGGAAACGUUA-5′ (SEQ ID NO: 2232)AAT-521 Target: 5′-AGTGAGCATCGCTACAGCCTTTGCAAT-3′ (SEQ ID NO:  2372)  5′-GAGCAUCGCUACAGCCUUUGCAAtg-3′ (SEQ ID NO: 2093)3′-CACUCGUAGCGAUGUCGGAAACGUUAC-5′ (SEQ ID NO: 2233)AAT-522 Target: 5′-GTGAGCATCGCTACAGCCTTTGCAATG-3′ (SEQ ID NO: 2373)  5′-AGCAUCGCUACAGCCUUUGCAAUgc-3′ (SEQ ID NO: 2094)3′-ACUCGUAGCGAUGUCGGAAACGUUACG-5′ (SEQ ID NO: 2234)AAT-523 Target: 5′-TGAGCATCGCTACAGCCTTTGCAATGC-3′ (SEQ ID NO: 2374)  5′-GCAUCGCUACAGCCUUUGCAAUGct-3′ (SEQ ID NO: 2095)3′-CUCGUAGCGAUGUCGGAAACGUUACGA-5′ (SEQ ID NO: 2235)AAT-524 Target: 5′-GAGCATCGCTACAGCCTTTGCAATGCT-3′ (SEQ ID NO: 2375)  5′-CAUCGCUACAGCCUUUGCAAUGCtC-3′ (SEQ ID NO: 2096)3′-UCGUAGCGAUGUCGGAAACGUUACGAG-5′ (SEQ ID NO: 2236)AAT-525 Target: 5′-AGCATCGCTACAGCCTTTGCAATGCTC-3′ (SEQ ID NO: 2376)  5′-AUCGCUACAGCCUUUGCAAUGCUct-3′ (SEQ ID NO: 2097)3′-CGUAGCGAUGUCGGAAACGUUACGAGA-5′ (SEQ ID NO: 2237)AAT-526 Target: 5′-GCATCGCTACAGCCTTTGCAATGCTCT-3′ (SEQ ID NO: 2377)  5′-UCGCUACAGCCUUUGCAAUGCUCtC-3′ (SEQ ID NO: 2098)3′-GUAGCGAUGUCGGAAACGUUACGAGAG-5′ (SEQ ID NO: 2238)AAT-527 Target: 5′-CATCGCTACAGCCTTTGCAATGCTCTC-3′ (SEQ ID NO: 2378)  5′-CGCUACAGCCUUUGCAAUGCUCUCC-3′ (SEQ ID NO: 2099)3′-UAGCGAUGUCGGAAACGUUACGAGAGG-5′ (SEQ ID NO: 2239)AAT-528 Target: 5′-ATCGCTACAGCCTTTGCAATGCTCTCC-3′ (SEQ ID NO: 2379)  5′-GCUACAGCCUUUGCAAUGCUCUCCC-3′ (SEQ ID NO: 2100)3′-AGCGAUGUCGGAAACGUUACGAGAGGG-5′ (SEQ ID NO: 2240)AAT-529 Target: 5′-TCGCTACAGCCTTTGCAATGCTCTCCC-3′ (SEQ ID NO: 2380)  5′-CUACAGCCUUUGCAAUGCUCUCCct-3′ (SEQ ID NO: 2101)3′-GCGAUGUCGGAAACGUUACGAGAGGGA-5′ (SEQ ID NO: 2241)AAT-530 Target: 5′-CGCTACAGCCTTTGCAATGCTCTCCCT-3′ (SEQ ID NO: 2381)  5′-UACAGCCUUUGCAAUGCUCUCCCtg-3′ (SEQ ID NO: 2102)3′-CGAUGUCGGAAACGUUACGAGAGGGAC-5′ (SEQ ID NO: 2242)AAT-531 Target: 5′-GCTACAGCCTTTGCAATGCTCTCCCTG-3′ (SEQ ID NO: 2382)  5′-CCUGGGGACCAAGGCUGACACUCac-3′ (SEQ ID NO: 2103)3′-AGGGACCCCUGGUUCCGACUGUGAGUG-5′ (SEQ ID NO: 2243)AAT-552 Target: 5′-TCCCTGGGGACCAAGGCTGACACTCAC-3′ (SEQ ID NO: 2383)  5′-GGGACCAAGGCUGACACUCACGAtg-3′ (SEQ ID NO: 2104)3′-ACCCCUGGUUCCGACUGUGAGUGCUAC-5′ (SEQ ID NO: 2244)AAT-556 Target: 5′-TGGGGACCAAGGCTGACACTCACGATG-3′ (SEQ ID NO: 2384)  5′-GGACCAAGGCUGACACUCACGAUga-3′ (SEQ ID NO: 2105)3′-CCCCUGGUUCCGACUGUGAGUGCUACU-5′ (SEQ ID NO: 2245)AAT-557 Target: 5′-GGGGACCAAGGCTGACACTCACGATGA-3′ (SEQ ID NO: 2385)  5′-GACCAAGGCUGACACUCACGAUGaa-3′ (SEQ ID NO: 2106)3′-CCCUGGUUCCGACUGUGAGUGCUACUU-5′ (SEQ ID NO: 2246)AAT-558 Target: 5′-GGGACCAAGGCTGACACTCACGATGAA-3′ (SEQ ID NO: 2386)  5′-UGAAAUCCUGGAGGGCCUGAAUUtC-3′ (SEQ ID NO: 2107)3′-CUACUUUAGGACCUCCCGGACUUAAAG-5′ (SEQ ID NO: 2247)AAT-579 Target: 5′-GATGAAATCCTGGAGGGCCTGAATTTC-3′ (SEQ ID NO: 2387)  5′-GAAAUCCUGGAGGGCCUGAAUUUca-3′ (SEQ ID NO: 2108)3′-UACUUUAGGACCUCCCGGACUUAAAGU-5′ (SEQ ID NO: 2248)AAT-580 Target: 5′-ATGAAATCCTGGAGGGCCTGAATTTCA-3′ (SEQ ID NO: 2388)  5′-UCCAUGAAGGCUUCCAGGAACUCct-3′ (SEQ ID NO: 2109)3′-CUAGGUACUUCCGAAGGUCCUUGAGGA-5′ (SEQ ID NO: 2249)AAT-632 Target: 5′-GATCCATGAAGGCTTCCAGGAACTCCT-3′ (SEQ ID NO: 2389)  5′-CCAUGAAGGCUUCCAGGAACUCCtc-3′ (SEQ ID NO: 2110)3′-UAGGUACUUCCGAAGGUCCUUGAGGAG-5′ (SEQ ID NO: 2250)AAT-633 Target: 5′-ATCCATGAAGGCTTCCAGGAACTCCTC-3′ (SEQ ID NO: 2390)  5′-GGACACCGAAGAGGCCAAGAAACag-3′ (SEQ ID NO: 2111)3′-CCCCUGUGGCUUCUCCGGUUCUUUGUC-5′ (SEQ ID NO: 2251)AAT-801 Target: 5′-GGGGACACCGAAGAGGCCAAGAAACAG-3′ (SEQ ID NO: 2391)  5′-GACACCGAAGAGGCCAAGAAACAga-3′ (SEQ ID NO: 2112)3′-CCCUGUGGCUUCUCCGGUUCUUUGUCU-5′ (SEQ ID NO: 2252)AAT-802 Target: 5′-GGGACACCGAAGAGGCCAAGAAACAGA-3′ (SEQ ID NO: 2392)  5′-ACACCGAAGAGGCCAAGAAACAGat-3′ (SEQ ID NO: 2113)3′-CCUGUGGCUUCUCCGGUUCUUUGUCUA-5′ (SEQ ID NO: 2253)AAT-803 Target: 5′-GGACACCGAAGAGGCCAAGAAACAGAT-3′ (SEQ ID NO: 2393)  5′-CACCGAAGAGGCCAAGAAACAGAtc-3′ (SEQ ID NO: 2114)3′-CUGUGGCUUCUCCGGUUCUUUGUCUAG-5′ (SEQ ID NO: 2254)AAT-804 Target: 5′-GACACCGAAGAGGCCAAGAAACAGATC-3′ (SEQ ID NO: 2394)  5′-ACCGAAGAGGCCAAGAAACAGAUca-3′ (SEQ ID NO: 2115)3′-UGUGGCUUCUCCGGUUCUUUGUCUAGU-5′ (SEQ ID NO: 2255)AAT-805 Target: 5′-ACACCGAAGAGGCCAAGAAACAGATCA-3′ (SEQ ID NO: 2395)  5′-CCGAAGAGGCCAAGAAACAGAUCaa-3′ (SEQ ID NO: 2116)3′-GUGGCUUCUCCGGUUCUUUGUCUAGUU-5′ (SEQ ID NO: 2256)AAT-806 Target: 5′-CACCGAAGAGGCCAAGAAACAGATCAA-3′ (SEQ ID NO: 2396)  5′-CGAAGAGGCCAAGAAACAGAUCAac-3′ (SEQ ID NO: 2117)3′-UGGCUUCUCCGGUUCUUUGUCUAGUUG-5′ (SEQ ID NO: 2257)AAT-807 Target: 5′-ACCGAAGAGGCCAAGAAACAGATCAAC-3′ (SEQ ID NO: 2397)  5′-GAAGAGGCCAAGAAACAGAUCAAcg-3′ (SEQ ID NO: 2118)3′-GGCUUCUCCGGUUCUUUGUCUAGUUGC-5′ (SEQ ID NO: 2258)AAT-808 Target: 5′-CCGAAGAGGCCAAGAAACAGATCAACG-3′ (SEQ ID NO: 2398)  5′-AAGAGGCCAAGAAACAGAUCAACga-3′ (SEQ ID NO: 2119)3′-GCUUCUCCGGUUCUUUGUCUAGUUGCU-5′ (SEQ ID NO: 2259)AAT-809 Target: 5′-CGAAGAGGCCAAGAAACAGATCAACGA-3′ (SEQ ID NO: 2399)  5′-AGAGGCCAAGAAACAGAUCAACGat-3′ (SEQ ID NO: 2120)3′-CUUCUCCGGUUCUUUGUCUAGUUGCUA-5′ (SEQ ID NO: 2260)AAT-810 Target: 5′-GAAGAGGCCAAGAAACAGATCAACGAT-3′ (SEQ ID NO: 2400)  5′-GAGGCCAAGAAACAGAUCAACGAtt-3′ (SEQ ID NO: 2121)3′-UUCUCCGGUUCUUUGUCUAGUUGCUAA-5′ (SEQ ID NO: 2261)AAT-811 Target: 5′-AAGAGGCCAAGAAACAGATCAACGATT-3′ (SEQ ID NO: 2401)  5′-AGGCCAAGAAACAGAUCAACGAUta-3′ (SEQ ID NO: 2122)3′-UCUCCGGUUCUUUGUCUAGUUGCUAAU-5′ (SEQ ID NO: 2262)AAT-812 Target: 5′-AGAGGCCAAGAAACAGATCAACGATTA-3′ (SEQ ID NO: 2402)  5′-GGCCAAGAAACAGAUCAACGAUUac-3′ (SEQ ID NO: 2123)3′-CUCCGGUUCUUUGUCUAGUUGCUAAUG-5′ (SEQ ID NO: 2263)AAT-813 Target: 5′-GAGGCCAAGAAACAGATCAACGATTAC-3′ (SEQ ID NO: 2403)  5′-UUUUGCUCUGGUGAAUUACAUCUtc-3′ (SEQ ID NO: 2124)3′-CAAAAACGAGACCACUUAAUGUAGAAG-5′ (SEQ ID NO: 2264)AAT-900 Target: 5′-GTTTTTGCTCTGGTGAATTACATCTTC-3′ (SEQ ID NO: 2404)  5′-UUUGCUCUGGUGAAUUACAUCUUct-3′ (SEQ ID NO: 2125)3′-AAAAACGAGACCACUUAAUGUAGAAGA-5′ (SEQ ID NO: 2265)AAT-901 Target: 5′-TTTTTGCTCTGGTGAATTACATCTTCT-3′ (SEQ ID NO: 2405)  5′-UUGCUCUGGUGAAUUACAUCUUCtt-3′ (SEQ ID NO: 2126)3′-AAAACGAGACCACUUAAUGUAGAAGAA-5′ (SEQ ID NO: 2266)AAT-902 Target: 5′-TTTTGCTCTGGTGAATTACATCTTCTT-3′ (SEQ ID NO: 2406)  5′-UGCUCUGGUGAAUUACAUCUUCUtt-3′ (SEQ ID NO: 2127)3′-AAACGAGACCACUUAAUGUAGAAGAAA-5′ (SEQ ID NO: 2267)AAT-903 Target: 5′-TTTGCTCTGGTGAATTACATCTTCTTT-3′ (SEQ ID NO: 2407)  5′-GCUCUGGUGAAUUACAUCUUCUUta-3′ (SEQ ID NO: 2128)3′-AACGAGACCACUUAAUGUAGAAGAAAU-5′ (SEQ ID NO: 2268)AAT-904 Target: 5′-TTGCTCTGGTGAATTACATCTTCTTTA-3′ (SEQ ID NO: 2408)  5′-CUCUGGUGAAUUACAUCUUCUUUaa-3′ (SEQ ID NO: 2129)3′-ACGAGACCACUUAAUGUAGAAGAAAUU-5′ (SEQ ID NO: 22 69)AAT-905 Target: 5′-TGCTCTGGTGAATTACATCTTCTTTAA-3′ (SEQ ID NO: 2409)  5′-UCUGGUGAAUUACAUCUUCUUUAaa-3′ (SEQ ID NO: 2130)3′-CGAGACCACUUAAUGUAGAAGAAAUUU-5′ (SEQ ID NO: 2270)AAT-906 Target: 5′-GCTCTGGTGAATTACATCTTCTTTAAA-3′ (SEQ ID NO: 2410)  5′-CUGGUGAAUUACAUCUUCUUUAAag-3′ (SEQ ID NO: 2131)3′-GAGACCACUUAAUGUAGAAGAAAUUUC-5′ (SEQ ID NO: 2271)AAT-907 Target: 5′-CTCTGGTGAATTACATCTTCTTTAAAG-3′ (SEQ ID NO: 2411)  5′-UGGUGAAUUACAUCUUCUUUAAAgg-3′ (SEQ ID NO: 2132)3′-AGACCACUUAAUGUAGAAGAAAUUUCC-5′ (SEQ ID NO: 2272)AAT-908 Target: 5′-TCTGGTGAATTACATCTTCTTTAAAGG-3′ (SEQ ID NO: 2412)  5′-GGUGAAUUACAUCUUCUUUAAAGgc-3′ (SEQ ID NO: 2133)3′-GACCACUUAAUGUAGAAGAAAUUUCCG-5′ (SEQ ID NO: 2273)AAT-909 Target: 5′-CTGGTGAATTACATCTTCTTTAAAGGC-3′ (SEQ ID NO: 2413)  5′-GUGAAUUACAUCUUCUUUAAAGGca-3′ (SEQ ID NO: 2134)3′-ACCACUUAAUGUAGAAGAAAUUUCCGU-5′ (SEQ ID NO: 2274)AAT-910 Target: 5′-TGGTGAATTACATCTTCTTTAAAGGCA-3′ (SEQ ID NO: 2414)  5′-UGAAUUACAUCUUCUUUAAAGGCaa-3′ (SEQ ID NO: 2135)3′-CCACUUAAUGUAGAAGAAAUUUCCGUU-5′ (SEQ ID NO: 2275)AAT-911 Target: 5′-GGTGAATTACATCTTCTTTAAAGGCAA-3′ (SEQ ID NO: 2415)  5′-GAAUUACAUCUUCUUUAAAGGCAaa-3′ (SEQ ID NO: 2136)3′-CACUUAAUGUAGAAGAAAUUUCCGUUU-5′ (SEQ ID NO: 2276)AAT-912 Target: 5′-GTGAATTACATCTTCTTTAAAGGCAAA-3′ (SEQ ID NO: 2416)  5′-AAUUACAUCUUCUUUAAAGGCAAat-3′ (SEQ ID NO: 2137)3′-ACUUAAUGUAGAAGAAAUUUCCGUUUA-5′ (SEQ ID NO: 2277)AAT-913 Target: 5′-TGAATTACATCTTCTTTAAAGGCAAAT-3′ (SEQ ID NO: 2417)  5′-AUUACAUCUUCUUUAAAGGCAAAtg-3′ (SEQ ID NO: 2138)3′-CUUAAUGUAGAAGAAAUUUCCGUUUAC-5′ (SEQ ID NO: 2278)AAT-914 Target: 5′-GAATTACATCTTCTTTAAAGGCAAATG-3′ (SEQ ID NO: 2418)  5′-UUACAUCUUCUUUAAAGGCAAAUgg-3′ (SEQ ID NO: 2139)3′-UUAAUGUAGAAGAAAUUUCCGUUUACC-5′ (SEQ ID NO: 2279)AAT-915 Target: 5′-AATTACATCTTCTTTAAAGGCAAATGG-3′ (SEQ ID NO: 2419)  5′-UACAUCUUCUUUAAAGGCAAAUGgg-3′ (SEQ ID NO: 2140)3′-UAAUGUAGAAGAAAUUUCCGUUUACCC-5′ (SEQ ID NO: 2280)AAT-916 Target: 5′-ATTACATCTTCTTTAAAGGCAAATGGG-3′ (SEQ ID NO: 2420)  5′-ACAUCUUCUUUAAAGGCAAAUGGga-3′ (SEQ ID NO: 2141)3′-AAUGUAGAAGAAAUUUCCGUUUACCCU-5′ (SEQ ID NO: 2281)AAT-917 Target: 5′-TTACATCTTCTTTAAAGGCAAATGGGA-3′ (SEQ ID NO: 2421)  5′-CAUCUUCUUUAAAGGCAAAUGGGag-3′ (SEQ ID NO: 2142)3′-AUGUAGAAGAAAUUUCCGUUUACCCUC-5′ (SEQ ID NO: 2282)AAT-918 Target: 5′-TACATCTTCTTTAAAGGCAAATGGGAG-3′ (SEQ ID NO: 2422)  5′-UUCUUUAAAGGCAAAUGGGAGAGac-3′ (SEQ ID NO: 2143)3′-AGAAGAAAUUUCCGUUUACCCUCUCUG-5′ (SEQ ID NO: 2283)AAT-922 Target: 5′-TCTTCTTTAAAGGCAAATGGGAGAGAC-3′ (SEQ ID NO: 2423)  5′-CUUUAAAGGCAAAUGGGAGAGACcC-3′ (SEQ ID NO: 2144)3′-AAGAAAUUUCCGUUUACCCUCUCUGGG-5′ (SEQ ID NO: 2284)AAT-924 Target: 5′-TTCTTTAAAGGCAAATGGGAGAGACCC-3′ (SEQ ID NO: 2424)  5′-GCAAAUGGGAGAGACCCUUUGAAgt-3′ (SEQ ID NO: 2145)3′-UCCGUUUACCCUCUCUGGGAAACUUCA-5′ (SEQ ID NO: 2285)AAT-932 Target: 5′-AGGCAAATGGGAGAGACCCTTTGAAGT-3′ (SEQ ID NO: 2425)  5′-CAAAUGGGAGAGACCCUUUGAAGtc-3′ (SEQ ID NO: 2146)3′-CCGUUUACCCUCUCUGGGAAACUUCAG-5′ (SEQ ID NO: 2286)AAT-933 Target: 5′-GGCAAATGGGAGAGACCCTTTGAAGTC-3′ (SEQ ID NO: 2426)  5′-AAAUGGGAGAGACCCUUUGAAGUca-3′ (SEQ ID NO: 2147)3′-CGUUUACCCUCUCUGGGAAACUUCAGU-5′ (SEQ ID NO: 2287)AAT-934 Target: 5′-GCAAATGGGAGAGACCCTTTGAAGTCA-3′ (SEQ ID NO: 2427)  5′-AAUGGGAGAGACCCUUUGAAGUCaa-3′ (SEQ ID NO: 2148)3′-GUUUACCCUCUCUGGGAAACUUCAGUU-5′ (SEQ ID NO: 2288)AAT-935 Target: 5′-CAAATGGGAGAGACCCTTTGAAGTCAA-3′ (SEQ ID NO: 2428)  5′-UGUCCAGCUGGGUGCUGCUGAUGaa-3′ (SEQ ID NO: 2149)3′-CGACAGGUCGACCCACGACGACUACUU-5′ (SEQ ID NO: 2289)AAT-1061 Target: 5′-GCTGTCCAGCTGGGTGCTGCTGATGAA-3′ (SEQ ID NO: 2429)  5′-GUCCAGCUGGGUGCUGCUGAUGAaa-3′ (SEQ ID NO: 2150)3′-GACAGGUCGACCCACGACGACUACUUU-5′ (SEQ ID NO: 2290)AAT-1062 Target: 5′-CTGTCCAGCTGGGTGCTGCTGATGAAA-3′ (SEQ ID NO: 2430)  5′-UCCAGCUGGGUGCUGCUGAUGAAat-3′ (SEQ ID NO: 2151)3′-ACAGGUCGACCCACGACGACUACUUUA-5′ (SEQ ID NO: 2291)AAT-1063 Target: 5′-TGTCCAGCTGGGTGCTGCTGATGAAAT-3′ (SEQ ID NO: 2431)  5′-CCAGCUGGGUGCUGCUGAUGAAAta-3′ (SEQ ID NO: 2152)3′-CAGGUCGACCCACGACGACUACUUUAU-5′ (SEQ ID NO: 2292)AAT-1064 Target: 5′-GTCCAGCTGGGTGCTGCTGATGAAATA-3′ (SEQ ID NO: 2432)  5′-CAGCUGGGUGCUGCUGAUGAAAUac-3′ (SEQ ID NO: 2153)3′-AGGUCGACCCACGACGACUACUUUAUG-5′ (SEQ ID NO: 2293)AAT-1065 Target: 5′-TCCAGCTGGGTGCTGCTGATGAAATAC-3′ (SEQ ID NO: 2433)  5′-AGCUGGGUGCUGCUGAUGAAAUACC-3′(SEQ ID NO: 2154)3′-GGUCGACCCACGACGACUACUUUAUGG-5′(SEQ ID NO: 2294)AAT-1066 Target: 5′-CCAGCTGGGTGCTGCTGATGAAATACC-3′ (SEQ ID NO: 2434)  5′-GCUGGGUGCUGCUGAUGAAAUACct-3′ (SEQ ID NO: 2155)3′-GUCGACCCACGACGACUACUUUAUGGA-5′ (SEQ ID NO: 2295)AAT-1067 Target: 5′-CAGCTGGGTGCTGCTGATGAAATACCT-3′ (SEQ ID NO: 2435)  5′-CUGGGUGCUGCUGAUGAAAUACCtg-3′ (SEQ ID NO: 2156)3′-UCGACCCACGACGACUACUUUAUGGAC-5′ (SEQ ID NO: 2296)AAT-1068 Target: 5′-AGCTGGGTGCTGCTGATGAAATACCTG-3′ (SEQ ID NO: 2436)  5′-UGGGUGCUGCUGAUGAAAUACCUgg-3′ (SEQ ID NO: 2157)3′-CGACCCACGACGACUACUUUAUGGACC-5′ (SEQ ID NO: 2297)AAT-1069 Target: 5′-GCTGGGTGCTGCTGATGAAATACCTGG-3′ (SEQ ID NO: 2437)  5′-GGGUGCUGCUGAUGAAAUACCUGgg-3′ (SEQ ID NO: 2158)3′-GACCCACGACGACUACUUUAUGGACCC-5′ (SEQ ID NO: 2298)AAT-1070 Target: 5′-CTGGGTGCTGCTGATGAAATACCTGGG-3′ (SEQ ID NO: 2438)  5′-GUGCUGCUGAUGAAAUACCUGGGca-3′ (SEQ ID NO: 2159)3′-CCCACGACGACUACUUUAUGGACCCGU-5′ (SEQ ID NO: 2299)AAT-1072 Target: 5′-GGGTGCTGCTGATGAAATACCTGGGCA-3′ (SEQ ID NO: 2439)  5′-UGCUGCUGAUGAAAUACCUGGGCaa-3′ (SEQ ID NO: 2160)3′-CCACGACGACUACUUUAUGGACCCGUU-5′ (SEQ ID NO: 2300)AAT-1073 Target: 5′-GGTGCTGCTGATGAAATACCTGGGCAA-3′ (SEQ ID NO: 2440)  5′-GCUGCUGAUGAAAUACCUGGGCAat-3′ (SEQ ID NO: 2161)3′-CACGACGACUACUUUAUGGACCCGUUA-5′ (SEQ ID NO: 2301)AAT-1074 Target: 5′-GTGCTGCTGATGAAATACCTGGGCAAT-3′ (SEQ ID NO: 2441)  5′-CUGCUGAUGAAAUACCUGGGCAAtg-3′ (SEQ ID NO: 2162)3′-ACGACGACUACUUUAUGGACCCGUUAC-5′ (SEQ ID NO: 2302)AAT-1075 Target: 5′-TGCTGCTGATGAAATACCTGGGCAATG-3′ (SEQ ID NO: 2442)  5′-UGCUGAUGAAAUACCUGGGCAAUgc-3′ (SEQ ID NO: 2163)3′-CGACGACUACUUUAUGGACCCGUUACG-5′ (SEQ ID NO: 2303)AAT-1076 Target: 5′-GCTGCTGATGAAATACCTGGGCAATGC-3′ (SEQ ID NO: 2443)  5′-GCUGAUGAAAUACCUGGGCAAUGCC-3′ (SEQ ID NO: 2164)3′-GACGACUACUUUAUGGACCCGUUACGG-5′ (SEQ ID NO: 2304)AAT-1077 Target: 5′-CTGCTGATGAAATACCTGGGCAATGCC-3′ (SEQ ID NO: 2444)  5′-CUGAUGAAAUACCUGGGCAAUGCca-3′ (SEQ ID NO: 2165)3′-ACGACUACUUUAUGGACCCGUUACGGU-5′ (SEQ ID NO: 2305)AAT-1078 Target: 5′-TGCTGATGAAATACCTGGGCAATGCCA-3′ (SEQ ID NO: 2445)  5′-UGAUGAAAUACCUGGGCAAUGCCac-3′ (SEQ ID NO: 2166)3′-CGACUACUUUAUGGACCCGUUACGGUG-5′ (SEQ ID NO: 2306)AAT-1079 Target: 5′-GCTGATGAAATACCTGGGCAATGCCAC-3′ (SEQ ID NO: 2446)  5′-GAUGAAAUACCUGGGCAAUGCCACC-3′ (SEQ ID NO: 2167)3′-GACUACUUUAUGGACCCGUUACGGUGG-5′ (SEQ ID NO: 2307)AAT-1080 Target: 5′-CTGATGAAATACCTGGGCAATGCCACC-3′ (SEQ ID NO: 2447)  5′-AUGAAAUACCUGGGCAAUGCCACcg-3′ (SEQ ID NO: 2168)3′-ACUACUUUAUGGACCCGUUACGGUGGC-5′ (SEQ ID NO: 2308)AAT-1081 Target: 5′-TGATGAAATACCTGGGCAATGCCACCG-3′(SEQ ID NO: 2448)  5′-GAAAUACCUGGGCAAUGCCACCGCC-3′ (SEQ ID NO: 2169)3′-UACUUUAUGGACCCGUUACGGUGGCGG-5′ (SEQ ID NO: 2309)AAT-1083 Target: 5′-ATGAAATACCTGGGCAATGCCACCGCC-3′ (SEQ ID NO: 2449)  5′-CAGCACCUGGAAAAUGAACUCACcC-3′ (SEQ ID NO: 2170)3′-AUGUCGUGGACCUUUUACUUGAGUGGG-5′ (SEQ ID NO: 2310)AAT-1138 Target: 5′-TACAGCACCTGGAAAATGAACTCACCC-3′(SEQ ID NO: 2450)  5′-CUGGAAAAUGAACUCACCCACGAta-3′ (SEQ ID NO: 2171)3′-UGGACCUUUUACUUGAGUGGGUGCUAU-5′ (SEQ ID NO: 2311)AAT-1144 Target: 5′-ACCTGGAAAATGAACTCACCCACGATA-3′ (SEQ ID NO: 2451)  5′-UGGAAAAUGAACUCACCCACGAUat-3′ (SEQ ID NO: 2172)3′-GGACCUUUUACUUGAGUGGGUGCUAUA-5′ (SEQ ID NO: 2312)AAT-1145 Target: 5′-CCTGGAAAATGAACTCACCCACGATAT-3′(SEQ ID NO: 2452)  5′-GAUAUCAUCACCAAGUUCCUGGAaa-3′ (SEQ ID NO: 2173)3′-UGCUAUAGUAGUGGUUCAAGGACCUUU-5′ (SEQ ID NO: 2313)AAT-1165 Target: 5′-ACGATATCATCACCAAGTTCCTGGAAA-3′ (SEQ ID NO: 2453)  5′-CAAGUUCCUGGAAAAUGAAGACAga-3′ (SEQ ID NO: 2174)3′-UGGUUCAAGGACCUUUUACUUCUGUCU-5′ (SEQ ID NO: 2314)AAT-1176 Target: 5′-ACCAAGTTCCTGGAAAATGAAGACAGA-3′ (SEQ ID NO: 2454)  5′-CCAUUACUGGAACCUAUGAUCUGaa-3′ (SEQ ID NO: 2175)3′-CAGGUAAUGACCUUGGAUACUAGACUU-5′ (SEQ ID NO: 2315)AAT-1232 Target: 5′-GTCCATTACTGGAACCTATGATCTGAA-3′ (SEQ ID NO: 2455)  5′-CAUUACUGGAACCUAUGAUCUGAag-3′ (SEQ ID NO: 2176)3′-AGGUAAUGACCUUGGAUACUAGACUUC-5′ (SEQ ID NO: 2316)AAT-1233 Target: 5′-TCCATTACTGGAACCTATGATCTGAAG-3′ (SEQ ID NO: 2456)  5′-AUUACUGGAACCUAUGAUCUGAAga-3′ (SEQ ID NO: 2177)3′-GGUAAUGACCUUGGAUACUAGACUUCU-5′ (SEQ ID NO: 2317)AAT-1234 Target: 5′-CCATTACTGGAACCTATGATCTGAAGA-3′ (SEQ ID NO: 2457)  5′-UUACUGGAACCUAUGAUCUGAAGag-3′ (SEQ ID NO: 2178)3′-GUAAUGACCUUGGAUACUAGACUUCUC-5′ (SEQ ID NO: 2318)AAT-1235 Target: 5′-CATTACTGGAACCTATGATCTGAAGAG-3′ (SEQ ID NO: 2458)  5′-UACUGGAACCUAUGAUCUGAAGAgc-3′ (SEQ ID NO: 2179)3′-UAAUGACCUUGGAUACUAGACUUCUCG-5′ (SEQ ID NO: 2319)AAT-1236 Target: 5′-ATTACTGGAACCTATGATCTGAAGAGC-3′ (SEQ ID NO: 2459)  5′-ACUGGAACCUAUGAUCUGAAGAGcg-3′ (SEQ ID NO: 2180)3′-AAUGACCUUGGAUACUAGACUUCUCGC-5′ (SEQ ID NO: 2320)AAT-1237 Target: 5′-TTACTGGAACCTATGATCTGAAGAGCG-3′ (SEQ ID NO: 2460)  5′-CUGGAACCUAUGAUCUGAAGAGCgt-3′ (SEQ ID NO: 2181)3′-AUGACCUUGGAUACUAGACUUCUCGCA-5′ (SEQ ID NO: 2321)AAT-1238 Target: 5′-TACTGGAACCTATGATCTGAAGAGCGT-3′ (SEQ ID NO: 2461)  5′-UGGAACCUAUGAUCUGAAGAGCGtc-3′ (SEQ ID NO: 2182)3′-UGACCUUGGAUACUAGACUUCUCGCAG-5′ (SEQ ID NO: 2322)AAT-1239 Target: 5′-ACTGGAACCTATGATCTGAAGAGCGTC-3′ (SEQ ID NO: 2462)  5′-GGAACCUAUGAUCUGAAGAGCGUcC-3′ (SEQ ID NO: 2183)3′-GACCUUGGAUACUAGACUUCUCGCAGG-5′ (SEQ ID NO: 2323)AAT-1240 Target: 5′-CTGGAACCTATGATCTGAAGAGCGTCC-3′ (SEQ ID NO: 2463)  5′-AUCACUAAGGUCUUCAGCAAUGGgg-3′ (SEQ ID NO: 2184)3′-CGUAGUGAUUCCAGAAGUCGUUACCCC-5′ (SEQ ID NO: 2324)AAT-1279 Target: 5′-GCATCACTAAGGTCTTCAGCAATGGGG-3′ (SEQ ID NO: 2464)  5′-UCACUAAGGUCUUCAGCAAUGGGgc-3′ (SEQ ID NO: 2185)3′-GUAGUGAUUCCAGAAGUCGUUACCCCG-5′ (SEQ ID NO: 2325)AAT-1280 Target: 5′-CATCACTAAGGTCTTCAGCAATGGGGC-3′ (SEQ ID NO: 2465)  5′-CACUAAGGUCUUCAGCAAUGGGGct-3′ (SEQ ID NO: 2186)3′-UAGUGAUUCCAGAAGUCGUUACCCCGA-5′ (SEQ ID NO: 2326)AAT-1281 Target: 5′-ATCACTAAGGTCTTCAGCAATGGGGCT-3′ (SEQ ID NO: 2466)  5′-CUAAGGUCUUCAGCAAUGGGGCUga-3′ (SEQ ID NO: 2187)3′-GUGAUUCCAGAAGUCGUUACCCCGACU-5′ (SEQ ID NO: 2327)AAT-1283 Target: 5′-CACTAAGGTCTTCAGCAATGGGGCTGA-3′ (SEQ ID NO: 2467)  5′-UAAGGUCUUCAGCAAUGGGGCUGac-3′ (SEQ ID NO: 2188)3′-UGAUUCCAGAAGUCGUUACCCCGACUG-5′ (SEQ ID NO: 2328)AAT-1284 Target: 5′-ACTAAGGTCTTCAGCAATGGGGCTGAC-3′ (SEQ ID NO: 2468)  5′-UGAAGCUCUCCAAGGCCGUGCAUaa-3′ (SEQ ID NO: 2189)3′-GGACUUCGAGAGGUUCCGGCACGUAUU-5′ (SEQ ID NO: 2329)AAT-1337 Target: 5′-CCTGAAGCTCTCCAAGGCCGTGCATAA-3′ (SEQ ID NO: 2469)  5′-GAAGCUCUCCAAGGCCGUGCAUAag-3′ (SEQ ID NO: 2190)3′-GACUUCGAGAGGUUCCGGCACGUAUUC-5′ (SEQ ID NO: 2330)AAT-1338 Target: 5′-CTGAAGCTCTCCAAGGCCGTGCATAAG-3′ (SEQ ID NO: 2470)  5′-AAGCUCUCCAAGGCCGUGCAUAAgg-3′ (SEQ ID NO: 2191)3′-ACUUCGAGAGGUUCCGGCACGUAUUCC-5′ (SEQ ID NO: 2331)AAT-1339 Target: 5′-TGAAGCTCTCCAAGGCCGTGCATAAGG-3′ (SEQ ID NO: 2471)  5′-CCGAGGUCAAGUUCAACAAACCCtt-3′ (SEQ ID NO: 2192)3′-GGGGCUCCAGUUCAAGUUGUUUGGGAA-5′ (SEQ ID NO: 2332)AAT-1442 Target: 5′-CCCCGAGGTCAAGTTCAACAAACCCTT-3′ (SEQ ID NO: 2472)  5′-CGAGGUCAAGUUCAACAAACCCUtt-3′ (SEQ ID NO: 2193)3′-GGGCUCCAGUUCAAGUUGUUUGGGAAA-5′ (SEQ ID NO: 2333)AAT-1443 Target: 5′-CCCGAGGTCAAGTTCAACAAACCCTTT-3′ (SEQ ID NO: 2473)  5′-GAGGUCAAGUUCAACAAACCCUUtg-3′ (SEQ ID NO: 2194)3′-GGCUCCAGUUCAAGUUGUUUGGGAAAC-5′ (SEQ ID NO: 2334)AAT-1444 Target: 5′-CCGAGGTCAAGTTCAACAAACCCTTTG-3′ (SEQ ID NO: 2474)  5′-AGGUCAAGUUCAACAAACCCUUUgt-3′ (SEQ ID NO: 2195)3′-GCUCCAGUUCAAGUUGUUUGGGAAACA-5′ (SEQ ID NO: 2335)AAT-1445 Target: 5′-CGAGGTCAAGTTCAACAAACCCTTTGT-3′ (SEQ ID NO: 2475)  5′-GGUCAAGUUCAACAAACCCUUUGtc-3′ (SEQ ID NO: 2196)3′-CUCCAGUUCAAGUUGUUUGGGAAACAG-5′ (SEQ ID NO: 2336)AAT-1446 Target: 5′-GAGGTCAAGTTCAACAAACCCTTTGTC-3′ (SEQ ID NO: 2476)  5′-GUCAAGUUCAACAAACCCUUUGUct-3′ (SEQ ID NO: 2197)3′-UCCAGUUCAAGUUGUUUGGGAAACAGA-5′ (SEQ ID NO: 2337)AAT-1447 Target: 5′-AGGTCAAGTTCAACAAACCCTTTGTCT-3′ (SEQ ID NO: 2477)  5′-UCAAGUUCAACAAACCCUUUGUCtt-3′ (SEQ ID NO: 2198)3′-CCAGUUCAAGUUGUUUGGGAAACAGAA-5′ (SEQ ID NO: 2338)AAT-1448 Target: 5′-GGTCAAGTTCAACAAACCCTTTGTCTT-3′ (SEQ ID NO: 2478)  5′-CAAGUUCAACAAACCCUUUGUCUtc-3′ (SEQ ID NO: 2199)3′-CAGUUCAAGUUGUUUGGGAAACAGAAG-5′ (SEQ ID NO: 2339)AAT-1449 Target: 5′-GTCAAGTTCAACAAACCCTTTGTCTTC-3′ (SEQ ID NO: 2479)  5′-AAGUUCAACAAACCCUUUGUCUUct-3′ (SEQ ID NO: 2200)3′-AGUUCAAGUUGUUUGGGAAACAGAAGA-5′ (SEQ ID NO: 2340)AAT-1450 Target: 5′-TCAAGTTCAACAAACCCTTTGTCTTCT-3′ (SEQ ID NO: 2480)  5′-AGUUCAACAAACCCUUUGUCUUCtt-3′ (SEQ ID NO: 2201)3′-GUUCAAGUUGUUUGGGAAACAGAAGAA-5′ (SEQ ID NO: 2341)AAT-1451 Target: 5′-CAAGTTCAACAAACCCTTTGTCTTCTT-3′ (SEQ ID NO: 2481)

TABLE 13 Further Human Anti-α-1 antitrypsin DsiRNAs, Unmodified Duplexes(Asymmetries) 5′-CCAGGGAGAUGCUGCCCAGAAGACA-3′ (SEQ ID NO: 2482)3′-GGGGUCCCUCUACGACGGGUCUUCUGU-5′ (SEQ ID NO: 2202)AAT-366 Target: 5′-CCCCAGGGAGATGCTGCCCAGAAGACA-3′ (SEQ ID NO: 2342)5′-CAGGGAGAUGCUGCCCAGAAGACAG-3′ (SEQ ID NO: 2483)3′-GGGUCCCUCUACGACGGGUCUUCUGUC-5′ (SEQ ID NO: 2203)AAT-367 Target: 5′-CCCAGGGAGATGCTGCCCAGAAGACAG-3′ (SEQ ID NO: 2343)5′-AGGGAGAUGCUGCCCAGAAGACAGA-3′ (SEQ ID NO: 2484)3′-GGUCCCUCUACGACGGGUCUUCUGUCU-5′ (SEQ ID NO: 2204)AAT-368 Target: 5′-CCAGGGAGATGCTGCCCAGAAGACAGA-3′ (SEQ ID NO: 2344)5′-GGGAGAUGCUGCCCAGAAGACAGAU-3′ (SEQ ID NO: 2485)3′-GUCCCUCUACGACGGGUCUUCUGUCUA-5′ (SEQ ID NO: 2205)AAT-369 Target: 5′-CAGGGAGATGCTGCCCAGAAGACAGAT-3′ (SEQ ID NO: 2345)5′-GGAGAUGCUGCCCAGAAGACAGAUA-3′ (SEQ ID NO: 2486)3′-UCCCUCUACGACGGGUCUUCUGUCUAU-5′ (SEQ ID NO: 2206)AAT-370 Target: 5′-AGGGAGATGCTGCCCAGAAGACAGATA-3′ (SEQ ID NO: 2346)5′-GAGAUGCUGCCCAGAAGACAGAUAC-3′ (SEQ ID NO: 2487)3′-CCCUCUACGACGGGUCUUCUGUCUAUG-5′ (SEQ ID NO: 2207)AAT-371 Target: 5′-GGGAGATGCTGCCCAGAAGACAGATAC-3′ (SEQ ID NO: 2347)5′-GAUACAUCCCACCAUGAUCAGGAUC-3′ (SEQ ID NO: 2488)3′-GUCUAUGUAGGGUGGUACUAGUCCUAG-5′ (SEQ ID NO: 2208)AAT-391 Target: 5′-CAGATACATCCCACCATGATCAGGATC-3′ (SEQ ID NO: 2348)5′-AUACAUCCCACCAUGAUCAGGAUCA-3′ (SEQ ID NO: 2489)3′-UCUAUGUAGGGUGGUACUAGUCCUAGU-5′ (SEQ ID NO: 2209)AAT-392 Target: 5′-AGATACATCCCACCATGATCAGGATCA-3′ (SEQ ID NO: 2349)5′-UACAUCCCACCAUGAUCAGGAUCAC-3′ (SEQ ID NO: 2490)3′-CUAUGUAGGGUGGUACUAGUCCUAGUG-5′ (SEQ ID NO: 2210)AAT-393 Target: 5′-GATACATCCCACCATGATCAGGATCAC-3′ (SEQ ID NO: 2350)5′-ACAUCCCACCAUGAUCAGGAUCACC-3′ (SEQ ID NO: 2491)3′-UAUGUAGGGUGGUACUAGUCCUAGUGG-5′ (SEQ ID NO: 2211)AAT-394 Target: 5′-ATACATCCCACCATGATCAGGATCACC-3′ (SEQ ID NO: 2351)5′-ACCAGUCCAACAGCACCAAUAUCUU-3′ (SEQ ID NO: 2492)3′-UGUGGUCAGGUUGUCGUGGUUAUAGAA-5′ (SEQ ID NO: 2212)AAT-485 Target: 5′-ACACCAGTCCAACAGCACCAATATCTT-3′ (SEQ ID NO: 2352)5′-CCAGUCCAACAGCACCAAUAUCUUC-3′ (SEQ ID NO: 2493)3′-GUGGUCAGGUUGUCGUGGUUAUAGAAG-5′ (SEQ ID NO: 2213)AAT-486 Target: 5′-CACCAGTCCAACAGCACCAATATCTTC-3′ (SEQ ID NO: 2353)5′-CAGUCCAACAGCACCAAUAUCUUCU-3′ (SEQ ID NO: 2494)3′-UGGUCAGGUUGUCGUGGUUAUAGAAGA-5′ (SEQ ID NO: 2214)AAT-487 Target: 5′-ACCAGTCCAACAGCACCAATATCTTCT-3′ (SEQ ID NO: 23545′-AGUCCAACAGCACCAAUAUCUUCUU-3′ (SEQ ID NO: 2495)3′-GGUCAGGUUGUCGUGGUUAUAGAAGAA-5′ (SEQ ID NO: 2215)AAT-488 Target: 5′-CCAGTCCAACAGCACCAATATCTTCTT-3′ (SEQ ID NO: 2355)5′-GUCCAACAGCACCAAUAUCUUCUUC-3′ (SEQ ID NO: 2496)3′-GUCAGGUUGUCGUGGUUAUAGAAGAAG-5′ (SEQ ID NO: 2216)AAT-489 Target: 5′-CAGTCCAACAGCACCAATATCTTCTTC-3′ (SEQ ID NO: 2356)5′-UCCAACAGCACCAAUAUCUUCUUCU-3′ (SEQ ID NO: 2497)3′-UCAGGUUGUCGUGGUUAUAGAAGAAGA-5′ (SEQ ID NO: 2217)AAT-490 Target: 5′-AGTCCAACAGCACCAATATCTTCTTCT-3′ (SEQ ID NO: 2357)5′-CCAACAGCACCAAUAUCUUCUUCUC-3′ (SEQ ID NO: 2498)3′-CAGGUUGUCGUGGUUAUAGAAGAAGAG-5′ (SEQ ID NO: 2218)AAT-491 Target: 5′-GTCCAACAGCACCAATATCTTCTTCTC-3′ (SEQ ID NO: 2358)5′-CAACAGCACCAAUAUCUUCUUCUCC-3′ (SEQ ID NO: 2499)3′-AGGUUGUCGUGGUUAUAGAAGAAGAGG-5′ (SEQ ID NO: 2219)AAT-492 Target: 5′-TCCAACAGCACCAATATCTTCTTCTCC-3′ (SEQ ID NO: 2359)5′-AACAGCACCAAUAUCUUCUUCUCCC-3′ (SEQ ID NO: 2500)3′-GGUUGUCGUGGUUAUAGAAGAAGAGGG-5′ (SEQ ID NO: 2220)AAT-493 Target: 5′-CCAACAGCACCAATATCTTCTTCTCCC-3′ (SEQ ID NO: 2360)5′-ACAGCACCAAUAUCUUCUUCUCCCC-3′ (SEQ ID NO: 2501)3′-GUUGUCGUGGUUAUAGAAGAAGAGGGG-5′ (SEQ ID NO: 2221)AAT-494 Target: 5′-CAACAGCACCAATATCTTCTTCTCCCC-3′ (SEQ ID NO: 2361)5′-CAGCACCAAUAUCUUCUUCUCCCCA-3′ (SEQ ID NO: 2502)3′-UUGUCGUGGUUAUAGAAGAAGAGGGGU-5′ (SEQ ID NO: 2222)AAT-495 Target: 5′-AACAGCACCAATATCTTCTTCTCCCCA-3′ (SEQ ID NO: 2362)5′-AGCACCAAUAUCUUCUUCUCCCCAG-3′ (SEQ ID NO: 2503)3′-UGUCGUGGUUAUAGAAGAAGAGGGGUC-5′ (SEQ ID NO: 2223)AAT-496 Target: 5′-ACAGCACCAATATCTTCTTCTCCCCAG-3′ (SEQ ID NO: 2363)5′-GCACCAAUAUCUUCUUCUCCCCAGU-3′ (SEQ ID NO: 2504)3′-GUCGUGGUUAUAGAAGAAGAGGGGUCA-5′ (SEQ ID NO: 2224)AAT-497 Target: 5′-CAGCACCAATATCTTCTTCTCCCCAGT-3′ (SEQ ID NO: 2364)5′-CACCAAUAUCUUCUUCUCCCCAGUG-3′ (SEQ ID NO: 2505)3′-UCGUGGUUAUAGAAGAAGAGGGGUCAC-5′ (SEQ ID NO: 2225)AAT-498 Target: 5′-AGCACCAATATCTTCTTCTCCCCAGTG-3′ (SEQ ID NO: 2365)5′-ACCAAUAUCUUCUUCUCCCCAGUGA-3′ (SEQ ID NO: 2506)3′-CGUGGUUAUAGAAGAAGAGGGGUCACU-5′ (SEQ ID NO: 2226)AAT-499 Target: 5′-GCACCAATATCTTCTTCTCCCCAGTGA-3′ (SEQ ID NO: 2366)5′-CCCAGUGAGCAUCGCUACAGCCUUU-3′ (SEQ ID NO: 2507)3′-AGGGGUCACUCGUAGCGAUGUCGGAAA-5′ (SEQ ID NO: 2227)AAT-516 Target: 5′-TCCCCAGTGAGCATCGCTACAGCCTTT-3′ (SEQ ID NO: 2367)5′-CCAGUGAGCAUCGCUACAGCCUUUG-3′ (SEQ ID NO: 2508)3′-GGGGUCACUCGUAGCGAUGUCGGAAAC-5′ (SEQ ID NO: 2228)AAT-517 Target: 5′-CCCCAGTGAGCATCGCTACAGCCTTTG-3′ (SEQ ID NO: 2368)5′-CAGUGAGCAUCGCUACAGCCUUUGC-3′ (SEQ ID NO: 2509)3′-GGGUCACUCGUAGCGAUGUCGGAAACG-5′ (SEQ ID NO: 2229)AAT-518 Target: 5′-CCCAGTGAGCATCGCTACAGCCTTTGC-3′ (SEQ ID NO: 2369)5′-AGUGAGCAUCGCUACAGCCUUUGCA-3′ (SEQ ID NO: 2510)3′-GGUCACUCGUAGCGAUGUCGGAAACGU-5′ (SEQ ID NO: 2230)AAT-519 Target: 5′-CCAGTGAGCATCGCTACAGCCTTTGCA-3′ (SEQ ID NO: 2370)5′-GUGAGCAUCGCUACAGCCUUUGCAA-3′ (SEQ ID NO: 2511)3′-GUCACUCGUAGCGAUGUCGGAAACGUU-5′ (SEQ ID NO: 2231)AAT-520 Target: 5′-CAGTGAGCATCGCTACAGCCTTTGCAA-3′ (SEQ ID NO: 2371)5′-UGAGCAUCGCUACAGCCUUUGCAAU-3′ (SEQ ID NO: 2512)3′-UCACUCGUAGCGAUGUCGGAAACGUUA-5′ (SEQ ID NO: 2232)AAT-521 Target: 5′-AGTGAGCATCGCTACAGCCTTTGCAAT-3′ (SEQ ID NO: 2372)5′-GAGCAUCGCUACAGCCUUUGCAAUG-3′ (SEQ ID NO: 2513)3′-CACUCGUAGCGAUGUCGGAAACGUUAC-5′ (SEQ ID NO: 2233)AAT-522 Target: 5′-GTGAGCATCGCTACAGCCTTTGCAATG-3′ (SEQ ID NO: 2373)5′-AGCAUCGCUACAGCCUUUGCAAUGC-3′ (SEQ ID NO: 2514)3′-ACUCGUAGCGAUGUCGGAAACGUUACG-5′ (SEQ ID NO: 2234)AAT-523 Target: 5′-TGAGCATCGCTACAGCCTTTGCAATGC-3′ (SEQ ID NO: 2374)5′-GCAUCGCUACAGCCUUUGCAAUGCU-3′ (SEQ ID NO: 2515)3′-CUCGUAGCGAUGUCGGAAACGUUACGA-5′ (SEQ ID NO: 2235)AAT-524 Target: 5′-GAGCATCGCTACAGCCTTTGCAATGCT-3′ (SEQ ID NO: 2375)5′-CAUCGCUACAGCCUUUGCAAUGCUC-3′ (SEQ ID NO: 2516)3′-UCGUAGCGAUGUCGGAAACGUUACGAG-5′ (SEQ ID NO: 2236)AAT-525 Target: 5′-AGCATCGCTACAGCCTTTGCAATGCTC-3′ (SEQ ID NO: 2376)5′-AUCGCUACAGCCUUUGCAAUGCUCU-3′ (SEQ ID NO: 2517)3′-CGUAGCGAUGUCGGAAACGUUACGAGA-5′ (SEQ ID NO: 2237)AAT-526 Target: 5′-GCATCGCTACAGCCTTTGCAATGCTCT-3′ (SEQ ID NO: 2377)5′-UCGCUACAGCCUUUGCAAUGCUCUC-3′ (SEQ ID NO: 2518)3′-GUAGCGAUGUCGGAAACGUUACGAGAG-5′ (SEQ ID NO: 2238)AAT-527 Target: 5′-CATCGCTACAGCCTTTGCAATGCTCTC-3′ (SEQ ID NO: 2378)5′-CGCUACAGCCUUUGCAAUGCUCUCC-3′ (SEQ ID NO: 2519)3′-UAGCGAUGUCGGAAACGUUACGAGAGG-5′ (SEQ ID NO: 2239)AAT-528 Target: 5′-ATCGCTACAGCCTTTGCAATGCTCTCC-3′ (SEQ ID NO: 2379)5′-GCUACAGCCUUUGCAAUGCUCUCCC-3′ (SEQ ID NO: 2520)3′-AGCGAUGUCGGAAACGUUACGAGAGGG-5′ (SEQ ID NO: 2240)AAT-529 Target: 5′-TCGCTACAGCCTTTGCAATGCTCTCCC-3′ (SEQ ID NO: 2380)5′-CUACAGCCUUUGCAAUGCUCUCCCU-3′ (SEQ ID NO: 2521)3′-GCGAUGUCGGAAACGUUACGAGAGGGA-5′ (SEQ ID NO: 2241)AAT-530 Target: 5′-CGCTACAGCCTTTGCAATGCTCTCCCT-3′ (SEQ ID NO: 2381)5′-UACAGCCUUUGCAAUGCUCUCCCUG-3′ (SEQ ID NO: 2522)3′-CGAUGUCGGAAACGUUACGAGAGGGAC-5′ (SEQ ID NO: 2242)AAT-531 Target: 5′-GCTACAGCCTTTGCAATGCTCTCCCTG-3′ (SEQ ID NO: 2382)5′-CCUGGGGACCAAGGCUGACACUCAC-3′ (SEQ ID NO: 2523)3′-AGGGACCCCUGGUUCCGACUGUGAGUG-5′ (SEQ ID NO: 2243)AAT-552 Target: 5′-TCCCTGGGGACCAAGGCTGACACTCAC-3′ (SEQ ID NO: 2383)5′-GGGACCAAGGCUGACACUCACGAUG-3′ (SEQ ID NO: 2 524)3′-ACCCCUGGUUCCGACUGUGAGUGCUAC-5′ (SEQ ID NO: 2244)AAT-556 Target: 5′-TGGGGACCAAGGCTGACACTCACGATG-3′ (SEQ ID NO: 2384)5′-GGACCAAGGCUGACACUCACGAUGA-3′ (SEQ ID NO: 2 525)3′-CCCCUGGUUCCGACUGUGAGUGCUACU-5′ (SEQ ID NO: 2245)AAT-557 Target: 5′-GGGGACCAAGGCTGACACTCACGATGA-3′ (SEQ ID NO: 2385)5′-GACCAAGGCUGACACUCACGAUGAA-3′ (SEQ ID NO: 2 526)3′-CCCUGGUUCCGACUGUGAGUGCUACUU-5′ (SEQ ID NO: 2246)AAT-558 Target: 5′-GGGACCAAGGCTGACACTCACGATGAA-3′ (SEQ ID NO: 2386)5′-UGAAAUCCUGGAGGGCCUGAAUUUC-3′ (SEQ ID NO: 2 527)3′-CUACUUUAGGACCUCCCGGACUUAAAG-5′ (SEQ ID NO: 2247)AAT-579 Target: 5′-GATGAAATCCTGGAGGGCCTGAATTTC-3′ (SEQ ID NO: 2387)5′-GAAAUCCUGGAGGGCCUGAAUUUCA-3′ (SEQ ID NO: 2 528)3′-UACUUUAGGACCUCCCGGACUUAAAGU-5′ (SEQ ID NO: 2248)AAT-580 Target: 5′-ATGAAATCCTGGAGGGCCTGAATTTCA-3′ (SEQ ID NO: 2388)5′-UCCAUGAAGGCUUCCAGGAACUCCU-3′ (SEQ ID NO: 2529)3′-CUAGGUACUUCCGAAGGUCCUUGAGGA-5′ (SEQ ID NO: 2249)AAT-632 Target: 5′-GATCCATGAAGGCTTCCAGGAACTCCT-3′ (SEQ ID NO: 2389)5′-CCAUGAAGGCUUCCAGGAACUCCUC-3′ (SEQ ID NO: 2530)3′-UAGGUACUUCCGAAGGUCCUUGAGGAG-5′ (SEQ ID NO: 2250)AAT-633 Target: 5′-ATCCATGAAGGCTTCCAGGAACTCCTC-3′ (SEQ ID NO: 2390)5′-GGACACCGAAGAGGCCAAGAAACAG-3′ (SEQ ID NO: 2531)3′-CCCCUGUGGCUUCUCCGGUUCUUUGUC-5′ (SEQ ID NO: 2251)AAT-801 Target: 5′-GGGGACACCGAAGAGGCCAAGAAACAG-3′ (SEQ ID NO: 2391)5′-GACACCGAAGAGGCCAAGAAACAGA-3′ (SEQ ID NO: 2532)3′-CCCUGUGGCUUCUCCGGUUCUUUGUCU-5′ (SEQ ID NO: 2252)AAT-802 Target: 5′-GGGACACCGAAGAGGCCAAGAAACAGA-3′ (SEQ ID NO: 2392)5′-ACACCGAAGAGGCCAAGAAACAGAU-3′ (SEQ ID NO: 2533)3′-CCUGUGGCUUCUCCGGUUCUUUGUCUA-5′ (SEQ ID NO: 2253)AAT-803 Target: 5′-GGACACCGAAGAGGCCAAGAAACAGAT-3′ (SEQ ID NO: 2393)5′-CACCGAAGAGGCCAAGAAACAGAUC-3′ (SEQ ID NO: 2534)3′-CUGUGGCUUCUCCGGUUCUUUGUCUAG-5′ (SEQ ID NO: 2254)AAT-804 Target: 5′-GACACCGAAGAGGCCAAGAAACAGATC-3′ (SEQ ID NO: 2394)5′-ACCGAAGAGGCCAAGAAACAGAUCA-3′ (SEQ ID NO: 2535)3′-UGUGGCUUCUCCGGUUCUUUGUCUAGU-5′ (SEQ ID NO: 2255)AAT-805 Target: 5′-ACACCGAAGAGGCCAAGAAACAGATCA-3′ (SEQ ID NO: 2395)5′-CCGAAGAGGCCAAGAAACAGAUCAA-3′ (SEQ ID NO: 2536)3′-GUGGCUUCUCCGGUUCUUUGUCUAGUU-5′ (SEQ ID NO: 2256)AAT-806 Target: 5′-CACCGAAGAGGCCAAGAAACAGATCAA-3′ (SEQ ID NO: 2396)5′-CGAAGAGGCCAAGAAACAGAUCAAC-3′ (SEQ ID NO: 2537)3′-UGGCUUCUCCGGUUCUUUGUCUAGUUG-5′ (SEQ ID NO: 2257)AAT-807 Target: 5′-ACCGAAGAGGCCAAGAAACAGATCAAC-3′ (SEQ ID NO: 2397)5′-GAAGAGGCCAAGAAACAGAUCAACG-3′ (SEQ ID NO: 2538)3′-GGCUUCUCCGGUUCUUUGUCUAGUUGC-5′ (SEQ ID NO: 2258)AAT-808 Target: 5′-CCGAAGAGGCCAAGAAACAGATCAACG-3′ (SEQ ID NO: 2398)5′-AAGAGGCCAAGAAACAGAUCAACGA-3′ (SEQ ID NO: 2539)3′-GCUUCUCCGGUUCUUUGUCUAGUUGCU-5′ (SEQ ID NO: 2259)AAT-809 Target: 5′-CGAAGAGGCCAAGAAACAGATCAACGA-3′ (SEQ ID NO: 2399)5′-AGAGGCCAAGAAACAGAUCAACGAU-3′ (SEQ ID NO: 2540)3′-CUUCUCCGGUUCUUUGUCUAGUUGCUA-5′ (SEQ ID NO: 2260)AAT-810 Target: 5′-GAAGAGGCCAAGAAACAGATCAACGAT-3′ (SEQ ID NO: 2400)5′-GAGGCCAAGAAACAGAUCAACGAUU-3′ (SEQ ID NO: 2541)3′-UUCUCCGGUUCUUUGUCUAGUUGCUAA-5′ (SEQ ID NO: 2261)AAT-811 Target: 5′-AAGAGGCCAAGAAACAGATCAACGATT-3′ (SEQ ID NO: 2401)5′-AGGCCAAGAAACAGAUCAACGAUUA-3′ (SEQ ID NO: 2542)3′-UCUCCGGUUCUUUGUCUAGUUGCUAAU-5′ (SEQ ID NO: 2262)AAT-812 Target: 5′-AGAGGCCAAGAAACAGATCAACGATTA-3′ (SEQ ID NO: 2402)5′-GGCCAAGAAACAGAUCAACGAUUAC-3′ (SEQ ID NO: 2543)3′-CUCCGGUUCUUUGUCUAGUUGCUAAUG-5′ (SEQ ID NO: 2263)AAT-813 Target: 5′-GAGGCCAAGAAACAGATCAACGATTAC-3′ (SEQ ID NO: 2403)5′-UUUUGCUCUGGUGAAUUACAUCUUC-3′ (SEQ ID NO: 2544)3′-CAAAAACGAGACCACUUAAUGUAGAAG-5′ (SEQ ID NO: 2264)AAT-900 Target: 5′-GTTTTTGCTCTGGTGAATTACATCTTC-3′ (SEQ ID NO: 2404)5′-UUUGCUCUGGUGAAUUACAUCUUCU-3′ (SEQ ID NO: 2545)3′-AAAAACGAGACCACUUAAUGUAGAAGA-5′ (SEQ ID NO: 2265)AAT-901 Target: 5′-TTTTTGCTCTGGTGAATTACATCTTCT-3′ (SEQ ID NO: 2405)5′-UUGCUCUGGUGAAUUACAUCUUCUU-3′ (SEQ ID NO: 2546)3′-AAAACGAGACCACUUAAUGUAGAAGAA-5′ (SEQ ID NO: 2266)AAT-902 Target: 5′-TTTTGCTCTGGTGAATTACATCTTCTT-3′ (SEQ ID NO: 2406)5′-UGCUCUGGUGAAUUACAUCUUCUUU-3′ (SEQ ID NO: 2547)3′-AAACGAGACCACUUAAUGUAGAAGAAA-5′ (SEQ ID NO: 2267)AAT-903 Target: 5′-TTTGCTCTGGTGAATTACATCTTCTTT-3′ (SEQ ID NO: 2407)5′-GCUCUGGUGAAUUACAUCUUCUUUA-3′ (SEQ ID NO: 2548)3′-AACGAGACCACUUAAUGUAGAAGAAAU-5′ (SEQ ID NO: 2268)AAT-904 Target: 5′-TTGCTCTGGTGAATTACATCTTCTTTA-3′ (SEQ ID NO: 2408)5′-CUCUGGUGAAUUACAUCUUCUUUAA-3′ (SEQ ID NO: 2549)3′-ACGAGACCACUUAAUGUAGAAGAAAUU-5′ (SEQ ID NO: 2269)AAT-905 Target: 5′-TGCTCTGGTGAATTACATCTTCTTTAA-3′ (SEQ ID NO: 2409)5′-UCUGGUGAAUUACAUCUUCUUUAAA-3′ (SEQ ID NO: 2550)3′-CGAGACCACUUAAUGUAGAAGAAAUUU-5′ (SEQ ID NO: 2270)AAT-906 Target: 5′-GCTCTGGTGAATTACATCTTCTTTAAA-3′ (SEQ ID NO: 2410)5′-CUGGUGAAUUACAUCUUCUUUAAAG-3′ (SEQ ID NO: 2551)3′-GAGACCACUUAAUGUAGAAGAAAUUUC-5′ (SEQ ID NO: 2271)AAT-907 Target: 5′-CTCTGGTGAATTACATCTTCTTTAAAG-3′ (SEQ ID NO: 2411)5′-UGGUGAAUUACAUCUUCUUUAAAGG-3′ (SEQ ID NO: 2552)3′-AGACCACUUAAUGUAGAAGAAAUUUCC-5′ (SEQ ID NO: 2272)AAT-908 Target: 5′-TCTGGTGAATTACATCTTCTTTAAAGG-3′ (SEQ ID NO: 2412)5′-GGUGAAUUACAUCUUCUUUAAAGGC-3′ (SEQ ID NO: 2553)3′-GACCACUUAAUGUAGAAGAAAUUUCCG-5′ (SEQ ID NO: 2273)AAT-909 Target: 5′-CTGGTGAATTACATCTTCTTTAAAGGC-3′ (SEQ ID NO: 2413)5′-GUGAAUUACAUCUUCUUUAAAGGCA-3′ (SEQ ID NO: 2554)3′-ACCACUUAAUGUAGAAGAAAUUUCCGU-5′ (SEQ ID NO: 2274)AAT-910 Target: 5′-TGGTGAATTACATCTTCTTTAAAGGCA-3′ (SEQ ID NO: 2414)5′-UGAAUUACAUCUUCUUUAAAGGCAA-3′ (SEQ ID NO: 2555)3′-CCACUUAAUGUAGAAGAAAUUUCCGUU-5′ (SEQ ID NO: 2275)AAT-911 Target: 5′-GGTGAATTACATCTTCTTTAAAGGCAA-3′ (SEQ ID NO: 2415)5′-GAAUUACAUCUUCUUUAAAGGCAAA-3′ (SEQ ID NO: 2556)3′-CACUUAAUGUAGAAGAAAUUUCCGUUU-5′ (SEQ ID NO: 2276)AAT-912 Target: 5′-GTGAATTACATCTTCTTTAAAGGCAAA-3′ (SEQ ID NO: 2416)5′-AAUUACAUCUUCUUUAAAGGCAAAU-3′ (SEQ ID NO: 2557)3′-ACUUAAUGUAGAAGAAAUUUCCGUUUA-5′ (SEQ ID NO: 2277)AAT-913 Target: 5′-TGAATTACATCTTCTTTAAAGGCAAAT-3′ (SEQ ID NO: 2417)5′-AUUACAUCUUCUUUAAAGGCAAAUG-3′ (SEQ ID NO: 2558)3′-CUUAAUGUAGAAGAAAUUUCCGUUUAC-5′ (SEQ ID NO: 2278)AAT-914 Target: 5′-GAATTACATCTTCTTTAAAGGCAAATG-3′ (SEQ ID NO: 2418)5′-UUACAUCUUCUUUAAAGGCAAAUGG-3′ (SEQ ID NO: 2559)3′-UUAAUGUAGAAGAAAUUUCCGUUUACC-5′ (SEQ ID NO: 2279)AAT-915 Target: 5′-AATTACATCTTCTTTAAAGGCAAATGG-3′ (SEQ ID NO: 2419)5′-UACAUCUUCUUUAAAGGCAAAUGGG-3′ (SEQ ID NO: 2560)3′-UAAUGUAGAAGAAAUUUCCGUUUACCC-5′ (SEQ ID NO: 2280)AAT-916 Target: 5′-ATTACATCTTCTTTAAAGGCAAATGGG-3′ (SEQ ID NO: 2420)5′-ACAUCUUCUUUAAAGGCAAAUGGGA-3′ (SEQ ID NO: 2561)3′-AAUGUAGAAGAAAUUUCCGUUUACCCU-5′ (SEQ ID NO: 2281)AAT-917 Target: 5′-TTACATCTTCTTTAAAGGCAAATGGGA-3′ (SEQ ID NO: 2421)5′-CAUCUUCUUUAAAGGCAAAUGGGAG-3′ (SEQ ID NO: 2562)3′-AUGUAGAAGAAAUUUCCGUUUACCCUC-5′ (SEQ ID NO: 2282)AAT-918 Target: 5′-TACATCTTCTTTAAAGGCAAATGGGAG-3′ (SEQ ID NO: 2422)5′-UUCUUUAAAGGCAAAUGGGAGAGAC-3′ (SEQ ID NO: 2563)3′-AGAAGAAAUUUCCGUUUACCCUCUCUG-5′ (SEQ ID NO: 2283)AAT-922 Target: 5′-TCTTCTTTAAAGGCAAATGGGAGAGAC-3′ (SEQ ID NO: 2423)5′-CUUUAAAGGCAAAUGGGAGAGACCC-3′ (SEQ ID NO: 2564)3′-AAGAAAUUUCCGUUUACCCUCUCUGGG-5′ (SEQ ID NO: 2284)AAT-924 Target: 5′-TTCTTTAAAGGCAAATGGGAGAGACCC-3′ (SEQ ID NO: 2424)5′-GCAAAUGGGAGAGACCCUUUGAAGU-3′ (SEQ ID NO: 2565)3′-UCCGUUUACCCUCUCUGGGAAACUUCA-5′ (SEQ ID NO: 2285)AAT-932 Target: 5′-AGGCAAATGGGAGAGACCCTTTGAAGT-3′ (SEQ ID NO: 2425)5′-CAAAUGGGAGAGACCCUUUGAAGUC-3′ (SEQ ID NO: 2566)3′-CCGUUUACCCUCUCUGGGAAACUUCAG-5′ (SEQ ID NO: 2286)AAT-933 Target: 5′-GGCAAATGGGAGAGACCCTTTGAAGTC-3′ (SEQ ID NO: 2426)5′-AAAUGGGAGAGACCCUUUGAAGUCA-3′ (SEQ ID NO: 2567)3′-CGUUUACCCUCUCUGGGAAACUUCAGU-5′ (SEQ ID NO: 2287)AAT-934 Target: 5′-GCAAATGGGAGAGACCCTTTGAAGTCA-3′ (SEQ ID NO: 2427)5′-AAUGGGAGAGACCCUUUGAAGUCAA-3′ (SEQ ID NO: 2568)3′-GUUUACCCUCUCUGGGAAACUUCAGUU-5′ (SEQ ID NO: 2288)AAT-935 Target: 5′-CAAATGGGAGAGACCCTTTGAAGTCAA-3′ (SEQ ID NO: 2428)5′-UGUCCAGCUGGGUGCUGCUGAUGAA-3′ (SEQ ID NO: 2569)3′-CGACAGGUCGACCCACGACGACUACUU-5′ (SEQ ID NO: 2289)AAT-1061 Target: 5′-GCTGTCCAGCTGGGTGCTGCTGATGAA-3′ (SEQ ID NO: 2429)5′-GUCCAGCUGGGUGCUGCUGAUGAAA-3′ (SEQ ID NO: 2570)3′-GACAGGUCGACCCACGACGACUACUUU-5′ (SEQ ID NO: 2290)AAT-1062 Target: 5′-CTGTCCAGCTGGGTGCTGCTGATGAAA-3′ (SEQ ID NO: 2430)5′-UCCAGCUGGGUGCUGCUGAUGAAAU-3′ (SEQ ID NO: 2571)3′-ACAGGUCGACCCACGACGACUACUUUA-5′ (SEQ ID NO: 2291)AAT-1063 Target: 5′-TGTCCAGCTGGGTGCTGCTGATGAAAT-3′ (SEQ ID NO: 2431)5′-CCAGCUGGGUGCUGCUGAUGAAAUA-3′ (SEQ ID NO: 2572)3′-CAGGUCGACCCACGACGACUACUUUAU-5′ (SEQ ID NO: 2292)AAT-1064 Target: 5′-GTCCAGCTGGGTGCTGCTGATGAAATA-3′ (SEQ ID NO: 2432)5′-CAGCUGGGUGCUGCUGAUGAAAUAC-3′ (SEQ ID NO: 2573)3′-AGGUCGACCCACGACGACUACUUUAUG-5′ (SEQ ID NO: 2293)AAT-1065 Target: 5′-TCCAGCTGGGTGCTGCTGATGAAATAC-3′ (SEQ ID NO: 2433)5′-AGCUGGGUGCUGCUGAUGAAAUACC-3′ (SEQ ID NO: 2574)3′-GGUCGACCCACGACGACUACUUUAUGG-5′ (SEQ ID NO: 2294)AAT-1066 Target: 5′-CCAGCTGGGTGCTGCTGATGAAATACC-3′ (SEQ ID NO: 2434)5′-GCUGGGUGCUGCUGAUGAAAUACCU-3′ (SEQ ID NO: 2575)3′-GUCGACCCACGACGACUACUUUAUGGA-5′ (SEQ ID NO: 2295)AAT-1067 Target: 5′-CAGCTGGGTGCTGCTGATGAAATACCT-3′ (SEQ ID NO: 2435)5′-CUGGGUGCUGCUGAUGAAAUACCUG-3′ (SEQ ID NO: 2576)3′-UCGACCCACGACGACUACUUUAUGGAC-5′ (SEQ ID NO: 2296)AAT-1068 Target: 5′-AGCTGGGTGCTGCTGATGAAATACCTG-3′ (SEQ ID NO: 2436)5′-UGGGUGCUGCUGAUGAAAUACCUGG-3′ (SEQ ID NO: 2577)3′-CGACCCACGACGACUACUUUAUGGACC-5′ (SEQ ID NO: 2297)AAT-1069 Target: 5′-GCTGGGTGCTGCTGATGAAATACCTGG-3′ (SEQ ID NO: 2437)5′-GGGUGCUGCUGAUGAAAUACCUGGG-3′ (SEQ ID NO: 2578)3′-GACCCACGACGACUACUUUAUGGACCC-5′ (SEQ ID NO: 2298)AAT-1070 Target: 5′-CTGGGTGCTGCTGATGAAATACCTGGG-3′ (SEQ ID NO: 2438)5′-GUGCUGCUGAUGAAAUACCUGGGCA-3′ (SEQ ID NO: 2579)3′-CCCACGACGACUACUUUAUGGACCCGU-5′ (SEQ ID NO: 2299)AAT-1072 Target: 5′-GGGTGCTGCTGATGAAATACCTGGGCA-3′ (SEQ ID NO: 2439)5′-UGCUGCUGAUGAAAUACCUGGGCAA-3′ (SEQ ID NO: 2580)3′-CCACGACGACUACUUUAUGGACCCGUU-5′ (SEQ ID NO: 2300)AAT-1073 Target: 5′-GGTGCTGCTGATGAAATACCTGGGCAA-3′ (SEQ ID NO: 2440)5′-GCUGCUGAUGAAAUACCUGGGCAAU-3′ (SEQ ID NO: 2581)3′-CACGACGACUACUUUAUGGACCCGUUA-5′ (SEQ ID NO: 2301)AAT-1074 Target: 5′-GTGCTGCTGATGAAATACCTGGGCAAT-3′ (SEQ ID NO: 2441)5′-CUGCUGAUGAAAUACCUGGGCAAUG-3′ (SEQ ID NO: 2582)3′-ACGACGACUACUUUAUGGACCCGUUAC-5′ (SEQ ID NO: 2302)AAT-1075 Target: 5′-TGCTGCTGATGAAATACCTGGGCAATG-3′ (SEQ ID NO: 2442)5′-UGCUGAUGAAAUACCUGGGCAAUGC-3′ (SEQ ID NO: 2583)3′-CGACGACUACUUUAUGGACCCGUUACG-5′ (SEQ ID NO: 2303)AAT-1076 Target: 5′-GCTGCTGATGAAATACCTGGGCAATGC-3′ (SEQ ID NO: 2443)5′-GCUGAUGAAAUACCUGGGCAAUGCC-3′ (SEQ ID NO: 2584)3′-GACGACUACUUUAUGGACCCGUUACGG-5′ (SEQ ID NO: 2304)AAT-1077 Target: 5′-CTGCTGATGAAATACCTGGGCAATGCC-3′ (SEQ ID NO: 2444)5′-CUGAUGAAAUACCUGGGCAAUGCCA-3′ (SEQ ID NO: 2585)3′-ACGACUACUUUAUGGACCCGUUACGGU-5′ (SEQ ID NO: 2305)AAT-1078 Target: 5′-TGCTGATGAAATACCTGGGCAATGCCA-3′ (SEQ ID NO: 2445)5′-UGAUGAAAUACCUGGGCAAUGCCAC-3′ (SEQ ID NO: 2586)3′-CGACUACUUUAUGGACCCGUUACGGUG-5′ (SEQ ID NO: 2306)AAT-1079 Target: 5′-GCTGATGAAATACCTGGGCAATGCCAC-3′ (SEQ ID NO: 2446)5′-GAUGAAAUACCUGGGCAAUGCCACC-3′ (SEQ ID NO: 2587)3′-GACUACUUUAUGGACCCGUUACGGUGG-5′ (SEQ ID NO: 2307)AAT-1080 Target: 5′-CTGATGAAATACCTGGGCAATGCCACC-3′ (SEQ ID NO: 2447)5′-AUGAAAUACCUGGGCAAUGCCACCG-3′ (SEQ ID NO: 2588)3′-ACUACUUUAUGGACCCGUUACGGUGGC-5′ (SEQ ID NO: 2308)AAT-1081 Target: 5′-TGATGAAATACCTGGGCAATGCCACCG-3′ (SEQ ID NO: 2448)5′-GAAAUACCUGGGCAAUGCCACCGCC-3′ (SEQ ID NO: 2589)3′-UACUUUAUGGACCCGUUACGGUGGCGG-5′ (SEQ ID NO: 2309)AAT-1083 Target: 5′-ATGAAATACCTGGGCAATGCCACCGCC-3′ (SEQ ID NO: 2449)5′-CAGCACCUGGAAAAUGAACUCACCC-3′ (SEQ ID NO: 2590)3′-AUGUCGUGGACCUUUUACUUGAGUGGG-5′ (SEQ ID NO: 2310)AAT-1138 Target: 5′-TACAGCACCTGGAAAATGAACTCACCC-3′ (SEQ ID NO: 2450)5′-CUGGAAAAUGAACUCACCCACGAUA-3′ (SEQ ID NO: 2591)3′-UGGACCUUUUACUUGAGUGGGUGCUAU-5′ (SEQ ID NO: 2311)AAT-1144 Target: 5′-ACCTGGAAAATGAACTCACCCACGATA-3′ (SEQ ID NO: 2451)5′-UGGAAAAUGAACUCACCCACGAUAU-3′ (SEQ ID NO: 2592)3′-GGACCUUUUACUUGAGUGGGUGCUAUA-5′ (SEQ ID NO: 2312)AAT-1145 Target: 5′-CCTGGAAAATGAACTCACCCACGATAT-3′ (SEQ ID NO: 2452)5′-GAUAUCAUCACCAAGUUCCUGGAAA-3′ (SEQ ID NO: 2593)3′-UGCUAUAGUAGUGGUUCAAGGACCUUU-5′ (SEQ ID NO: 2313)AAT-1165 Target: 5′-ACGATATCATCACCAAGTTCCTGGAAA-3′ (SEQ ID NO: 2453)5′-CAAGUUCCUGGAAAAUGAAGACAGA-3′ (SEQ ID NO: 2594)3′-UGGUUCAAGGACCUUUUACUUCUGUCU-5′ (SEQ ID NO: 2314)AAT-1176 Target: 5′-ACCAAGTTCCTGGAAAATGAAGACAGA-3′ (SEQ ID NO: 2454)5′-CCAUUACUGGAACCUAUGAUCUGAA-3′ (SEQ ID NO: 2595)3′-CAGGUAAUGACCUUGGAUACUAGACUU-5′ (SEQ ID NO: 2315)AAT-1232 Target: 5′-GTCCATTACTGGAACCTATGATCTGAA-3′ (SEQ ID NO: 2455)5′-CAUUACUGGAACCUAUGAUCUGAAG-3′ (SEQ ID NO: 2596)3′-AGGUAAUGACCUUGGAUACUAGACUUC-5′ (SEQ ID NO: 2316)AAT-1233 Target: 5′-TCCATTACTGGAACCTATGATCTGAAG-3′ (SEQ ID NO: 2456)5′-AUUACUGGAACCUAUGAUCUGAAGA-3′ (SEQ ID NO: 2597)3′-GGUAAUGACCUUGGAUACUAGACUUCU-5′ (SEQ ID NO: 2317)AAT-1234 Target: 5′-CCATTACTGGAACCTATGATCTGAAGA-3′ (SEQ ID NO: 2457)5′-UUACUGGAACCUAUGAUCUGAAGAG-3′ (SEQ ID NO: 2598)3′-GUAAUGACCUUGGAUACUAGACUUCUC-5′ (SEQ ID NO: 2318)AAT-1235 Target: 5′-CATTACTGGAACCTATGATCTGAAGAG-3′ (SEQ ID NO: 2458)5′-UACUGGAACCUAUGAUCUGAAGAGC-3′ (SEQ ID NO: 2599)3′-UAAUGACCUUGGAUACUAGACUUCUCG-5′ (SEQ ID NO: 2319)AAT-1236 Target: 5′-ATTACTGGAACCTATGATCTGAAGAGC-3′ (SEQ ID NO: 2459)5′-ACUGGAACCUAUGAUCUGAAGAGCG-3′ (SEQ ID NO: 2600)3′-AAUGACCUUGGAUACUAGACUUCUCGC-5′ (SEQ ID NO: 2320)AAT-1237 Target: 5′-TTACTGGAACCTATGATCTGAAGAGCG-3′ (SEQ ID NO: 2460)5′-CUGGAACCUAUGAUCUGAAGAGCGU-3′ (SEQ ID NO: 2601)3′-AUGACCUUGGAUACUAGACUUCUCGCA-5′ (SEQ ID NO: 2321)AAT-1238 Target: 5′-TACTGGAACCTATGATCTGAAGAGCGT-3′ (SEQ ID NO: 2461)5′-UGGAACCUAUGAUCUGAAGAGCGUC-3′ (SEQ ID NO: 2602)3′-UGACCUUGGAUACUAGACUUCUCGCAG-5′ (SEQ ID NO: 2322)AAT-1239 Target: 5′-ACTGGAACCTATGATCTGAAGAGCGTC-3′ (SEQ ID NO: 2462)5′-GGAACCUAUGAUCUGAAGAGCGUCC-3′ (SEQ ID NO: 2603)3′-GACCUUGGAUACUAGACUUCUCGCAGG-5′ (SEQ ID NO: 2323)AAT-1240 Target: 5′-CTGGAACCTATGATCTGAAGAGCGTCC-3′ (SEQ ID NO: 2463)5′-AUCACUAAGGUCUUCAGCAAUGGGG-3′ (SEQ ID NO: 2604)3′-CGUAGUGAUUCCAGAAGUCGUUACCCC-5′ (SEQ ID NO: 2324)AAT-1279 Target: 5′-GCATCACTAAGGTCTTCAGCAATGGGG-3′ (SEQ ID NO: 2464)5′-UCACUAAGGUCUUCAGCAAUGGGGC-3′ (SEQ ID NO: 2605)3′-GUAGUGAUUCCAGAAGUCGUUACCCCG-5′ (SEQ ID NO: 2325)AAT-1280 Target: 5′-CATCACTAAGGTCTTCAGCAATGGGGC-3′ (SEQ ID NO: 2465)5′-CACUAAGGUCUUCAGCAAUGGGGCU-3′ (SEQ ID NO: 2606)3′-UAGUGAUUCCAGAAGUCGUUACCCCGA-5′ (SEQ ID NO: 2326)AAT-1281 Target: 5′-ATCACTAAGGTCTTCAGCAATGGGGCT-3′ (SEQ ID NO: 2466)5′-CUAAGGUCUUCAGCAAUGGGGCUGA-3′ (SEQ ID NO: 2607)3′-GUGAUUCCAGAAGUCGUUACCCCGACU-5′ (SEQ ID NO: 2327)AAT-1283 Target: 5′-CACTAAGGTCTTCAGCAATGGGGCTGA-3′ (SEQ ID NO: 2467)5′-UAAGGUCUUCAGCAAUGGGGCUGAC-3′ (SEQ ID NO: 2608)3′-UGAUUCCAGAAGUCGUUACCCCGACUG-5′ (SEQ ID NO: 2328)AAT-1284 Target: 5′-ACTAAGGTCTTCAGCAATGGGGCTGAC-3′ (SEQ ID NO: 2468)5′-UGAAGCUCUCCAAGGCCGUGCAUAA-3′ (SEQ ID NO: 2609)3′-GGACUUCGAGAGGUUCCGGCACGUAUU-5′ (SEQ ID NO: 2329)AAT-1337 Target: 5′-CCTGAAGCTCTCCAAGGCCGTGCATAA-3′ (SEQ ID NO: 2469)5′-GAAGCUCUCCAAGGCCGUGCAUAAG-3′ (SEQ ID NO: 2610)3′-GACUUCGAGAGGUUCCGGCACGUAUUC-5′ (SEQ ID NO: 2330)AAT-1338 Target: 5′-CTGAAGCTCTCCAAGGCCGTGCATAAG-3′ (SEQ ID NO: 2470)5′-AAGCUCUCCAAGGCCGUGCAUAAGG-3′ (SEQ ID NO: 2611)3′-ACUUCGAGAGGUUCCGGCACGUAUUCC-5′ (SEQ ID NO: 2331)AAT-1339 Target: 5′-TGAAGCTCTCCAAGGCCGTGCATAAGG-3′ (SEQ ID NO: 2471)5′-CCGAGGUCAAGUUCAACAAACCCUU-3′ (SEQ ID NO: 2612)3′-GGGGCUCCAGUUCAAGUUGUUUGGGAA-5′ (SEQ ID NO: 2332)AAT-1442 Target: 5′-CCCCGAGGTCAAGTTCAACAAACCCTT-3′ (SEQ ID NO: 2472)5′-CGAGGUCAAGUUCAACAAACCCUUU-3′ (SEQ ID NO: 2613)3′-GGGCUCCAGUUCAAGUUGUUUGGGAAA-5′ (SEQ ID NO: 2333)AAT-1443 Target: 5′-CCCGAGGTCAAGTTCAACAAACCCTTT-3′ (SEQ ID NO: 2473)5′-GAGGUCAAGUUCAACAAACCCUUUG-3′ (SEQ ID NO: 2614)3′-GGCUCCAGUUCAAGUUGUUUGGGAAAC-5′ (SEQ ID NO: 2334)AAT-1444 Target: 5′-CCGAGGTCAAGTTCAACAAACCCTTTG-3′ (SEQ ID NO: 2474)5′-AGGUCAAGUUCAACAAACCCUUUGU-3′ (SEQ ID NO: 2615)3′-GCUCCAGUUCAAGUUGUUUGGGAAACA-5′ (SEQ ID NO: 2335)AAT-1445 Target: 5′-CGAGGTCAAGTTCAACAAACCCTTTGT-3′ (SEQ ID NO: 2475)5′-GGUCAAGUUCAACAAACCCUUUGUC-3′ (SEQ ID NO: 2616)3′-CUCCAGUUCAAGUUGUUUGGGAAACAG-5′ (SEQ ID NO: 2336)AAT-1446 Target: 5′-GAGGTCAAGTTCAACAAACCCTTTGTC-3′ (SEQ ID NO: 2476)5′-GUCAAGUUCAACAAACCCUUUGUCU-3′ (SEQ ID NO: 2617)3′-UCCAGUUCAAGUUGUUUGGGAAACAGA-5′ (SEQ ID NO: 2337)AAT-1447 Target: 5′-AGGTCAAGTTCAACAAACCCTTTGTCT-3′ (SEQ ID NO: 2477)5′-UCAAGUUCAACAAACCCUUUGUCUU-3′ (SEQ ID NO: 2618)3′-CCAGUUCAAGUUGUUUGGGAAACAGAA-5′ (SEQ ID NO: 2338)AAT-1448 Target: 5′-GGTCAAGTTCAACAAACCCTTTGTCTT-3′ (SEQ ID NO: 2478)5′-CAAGUUCAACAAACCCUUUGUCUUC-3′ (SEQ ID NO: 2619)3′-CAGUUCAAGUUGUUUGGGAAACAGAAG-5′ (SEQ ID NO: 2339)AAT-1449 Target: 5′-GTCAAGTTCAACAAACCCTTTGTCTTC-3′ (SEQ ID NO: 2479)5′-AAGUUCAACAAACCCUUUGUCUUCU-3′ (SEQ ID NO: 2620)3′-AGUUCAAGUUGUUUGGGAAACAGAAGA-5′ (SEQ ID NO: 2340)AAT-1450 Target: 5′-TCAAGTTCAACAAACCCTTTGTCTTCT-3′ (SEQ ID NO: 2480)5′-AGUUCAACAAACCCUUUGUCUUCUU-3′ (SEQ ID NO: 2621)3′-GUUCAAGUUGUUUGGGAAACAGAAGAA-5′ (SEQ ID NO: 2341)AAT-1451 Target: 5′-CAAGTTCAACAAACCCTTTGTCTTCTT-3′ (SEQ ID NO: 2481)

TABLE 14Further DsiRNA Target Sequences (21 mers) in α-1 antitrypsin mRNAAAT-366 21 nt Target: 5′-CCCCAGGGAGAUGCUGCCCAG-3′ (SEQ ID NO: 2622)AAT-367 21 nt Target: 5′-CCCAGGGAGAUGCUGCCCAGA-3′ (SEQ ID NO: 2623)AAT-368 21 nt Target: 5′-CCAGGGAGAUGCUGCCCAGAA-3′ (SEQ ID NO: 2624)AAT-369 21 nt Target: 5′-CAGGGAGAUGCUGCCCAGAAG-3′ (SEQ ID NO: 2625)AAT-370 21 nt Target: 5′-AGGGAGAUGCUGCCCAGAAGA-3′ (SEQ ID NO: 2626)AAT-371 21 nt Target: 5′-GGGAGAUGCUGCCCAGAAGAC-3′ (SEQ ID NO: 2627)AAT-391 21 nt Target: 5′-CAGAUACAUCCCACCAUGAUC-3′ (SEQ ID NO: 2628)AAT-392 21 nt Target: 5′-AGAUACAUCCCACCAUGAUCA-3′ (SEQ ID NO: 2629)AAT-393 21 nt Target: 5′-GAUACAUCCCACCAUGAUCAG-3′ (SEQ ID NO: 2630)AAT-394 21 nt Target: 5′-AUACAUCCCACCAUGAUCAGG-3′ (SEQ ID NO: 2631)AAT-485 21 nt Target: 5′-ACACCAGUCCAACAGCACCAA-3′ (SEQ ID NO: 2632)AAT-486 21 nt Target: 5′-CACCAGUCCAACAGCACCAAU-3′ (SEQ ID NO: 2633)AAT-487 21 nt Target: 5′-ACCAGUCCAACAGCACCAAUA-3′ (SEQ ID NO: 2634)AAT-488 21 nt Target: 5′-CCAGUCCAACAGCACCAAUAU-3′ (SEQ ID NO: 2635)AAT-489 21 nt Target: 5′-CAGUCCAACAGCACCAAUAUC-3′ (SEQ ID NO: 2636)AAT-490 21 nt Target: 5′-AGUCCAACAGCACCAAUAUCU-3′ (SEQ ID NO: 2637)AAT-491 21 nt Target: 5′-GUCCAACAGCACCAAUAUCUU-3′ (SEQ ID NO: 2638)AAT-492 21 nt Target: 5′-UCCAACAGCACCAAUAUCUUC-3′ (SEQ ID NO: 2639)AAT-493 21 nt Target: 5′-CCAACAGCACCAAUAUCUUCU-3′ (SEQ ID NO: 2640)AAT-494 21 nt Target: 5′-CAACAGCACCAAUAUCUUCUU-3′ (SEQ ID NO: 2641)AAT-495 21 nt Target: 5′-AACAGCACCAAUAUCUUCUUC-3′ (SEQ ID NO: 2642)AAT-496 21 nt Target: 5′-ACAGCACCAAUAUCUUCUUCU-3′ (SEQ ID NO: 2643)AAT-497 21 nt Target: 5′-CAGCACCAAUAUCUUCUUCUC-3′ (SEQ ID NO: 2644)AAT-498 21 nt Target: 5′-AGCACCAAUAUCUUCUUCUCC-3′ (SEQ ID NO: 2645)AAT-499 21 nt Target: 5′-GCACCAAUAUCUUCUUCUCCC-3′ (SEQ ID NO: 2646)AAT-516 21 nt Target: 5′-UCCCCAGUGAGCAUCGCUACA-3′ (SEQ ID NO: 2647)AAT-517 21 nt Target: 5′-CCCCAGUGAGCAUCGCUACAG-3′ (SEQ ID NO: 2648)AAT-518 21 nt Target: 5′-CCCAGUGAGCAUCGCUACAGC-3′ (SEQ ID NO: 2649)AAT-519 21 nt Target: 5′-CCAGUGAGCAUCGCUACAGCC-3′ (SEQ ID NO: 2650)AAT-520 21 nt Target: 5′-CAGUGAGCAUCGCUACAGCCU-3′ (SEQ ID NO: 2651)AAT-521 21 nt Target: 5′-AGUGAGCAUCGCUACAGCCUU-3′ (SEQ ID NO: 2652)AAT-522 21 nt Target: 5′-GUGAGCAUCGCUACAGCCUUU-3′ (SEQ ID NO: 2653)AAT-523 21 nt Target: 5′-UGAGCAUCGCUACAGCCUUUG-3′ (SEQ ID NO: 2654)AAT-524 21 nt Target: 5′-GAGCAUCGCUACAGCCUUUGC-3′ (SEQ ID NO: 2655)AAT-525 21 nt Target: 5′-AGCAUCGCUACAGCCUUUGCA-3′ (SEQ ID NO: 2656)AAT-526 21 nt Target: 5′-GCAUCGCUACAGCCUUUGCAA-3′ (SEQ ID NO: 2657)AAT-527 21 nt Target: 5′-CAUCGCUACAGCCUUUGCAAU-3′ (SEQ ID NO: 2658)AAT-528 21 nt Target: 5′-AUCGCUACAGCCUUUGCAAUG-3′ (SEQ ID NO: 2659)AAT-529 21 nt Target: 5′-UCGCUACAGCCUUUGCAAUGC-3′ (SEQ ID NO: 2660)AAT-530 21 nt Target: 5′-CGCUACAGCCUUUGCAAUGCU-3′ (SEQ ID NO: 2661)AAT-531 21 nt Target: 5′-GCUACAGCCUUUGCAAUGCUC-3′ (SEQ ID NO: 2662)AAT-552 21 nt Target: 5′-UCCCUGGGGACCAAGGCUGAC-3′ (SEQ ID NO: 2663)AAT-556 21 nt Target: 5′-UGGGGACCAAGGCUGACACUC-3′ (SEQ ID NO: 2664)AAT-557 21 nt Target: 5′-GGGGACCAAGGCUGACACUCA-3′ (SEQ ID NO: 2665)AAT-558 21 nt Target: 5′-GGGACCAAGGCUGACACUCAC-3′ (SEQ ID NO: 2666)AAT-579 21 nt Target: 5′-GAUGAAAUCCUGGAGGGCCUG-3′ (SEQ ID NO: 2667)AAT-580 21 nt Target: 5′-AUGAAAUCCUGGAGGGCCUGA-3′ (SEQ ID NO: 2668)AAT-632 21 nt Target: 5′-GAUCCAUGAAGGCUUCCAGGA-3′ (SEQ ID NO: 2669)AAT-633 21 nt Target: 5′-AUCCAUGAAGGCUUCCAGGAA-3′ (SEQ ID NO: 2670)AAT-801 21 nt Target: 5′-GGGGACACCGAAGAGGCCAAG-3′ (SEQ ID NO: 2671)AAT-802 21 nt Target: 5′-GGGACACCGAAGAGGCCAAGA-3′ (SEQ ID NO: 2672)AAT-803 21 nt Target: 5′-GGACACCGAAGAGGCCAAGAA-3′ (SEQ ID NO: 2673)AAT-804 21 nt Target: 5′-GACACCGAAGAGGCCAAGAAA-3′ (SEQ ID NO: 2674)AAT-805 21 nt Target: 5′-ACACCGAAGAGGCCAAGAAAC-3′ (SEQ ID NO: 2675)AAT-806 21 nt Target: 5′-CACCGAAGAGGCCAAGAAACA-3′ (SEQ ID NO: 2676)AAT-807 21 nt Target: 5′-ACCGAAGAGGCCAAGAAACAG-3′ (SEQ ID NO: 2677)AAT-808 21 nt Target: 5′-CCGAAGAGGCCAAGAAACAGA-3′ (SEQ ID NO: 2678)AAT-809 21 nt Target: 5′-CGAAGAGGCCAAGAAACAGAU-3′ (SEQ ID NO: 2679)AAT-810 21 nt Target: 5′-GAAGAGGCCAAGAAACAGAUC-3′ (SEQ ID NO: 2680)AAT-811 21 nt Target: 5′-AAGAGGCCAAGAAACAGAUCA-3′ (SEQ ID NO: 2681)AAT-812 21 nt Target: 5′-AGAGGCCAAGAAACAGAUCAA-3′ (SEQ ID NO: 2682)AAT-813 21 nt Target: 5′-GAGGCCAAGAAACAGAUCAAC-3′ (SEQ ID NO: 2683)AAT-900 21 nt Target: 5′-GUUUUUGCUCUGGUGAAUUAC-3′ (SEQ ID NO: 2684)AAT-901 21 nt Target: 5′-UUUUUGCUCUGGUGAAUUACA-3′ (SEQ ID NO: 2685)AAT-902 21 nt Target: 5′-UUUUGCUCUGGUGAAUUACAU-3′ (SEQ ID NO: 2686)AAT-903 21 nt Target: 5′-UUUGCUCUGGUGAAUUACAUC-3′ (SEQ ID NO: 2687)AAT-904 21 nt Target: 5′-UUGCUCUGGUGAAUUACAUCU-3′ (SEQ ID NO: 2688)AAT-905 21 nt Target: 5′-UGCUCUGGUGAAUUACAUCUU-3′ (SEQ ID NO: 2689)AAT-906 21 nt Target: 5′-GCUCUGGUGAAUUACAUCUUC-3′ (SEQ ID NO: 2690)AAT-907 21 nt Target: 5′-CUCUGGUGAAUUACAUCUUCU-3′ (SEQ ID NO: 2691)AAT-908 21 nt Target: 5′-UCUGGUGAAUUACAUCUUCUU-3′ (SEQ ID NO: 2692)AAT-909 21 nt Target: 5′-CUGGUGAAUUACAUCUUCUUU-3′ (SEQ ID NO: 2693)AAT-910 21 nt Target: 5′-UGGUGAAUUACAUCUUCUUUA-3′ (SEQ ID NO: 2694)AAT-911 21 nt Target: 5′-GGUGAAUUACAUCUUCUUUAA-3′ (SEQ ID NO: 2695)AAT-912 21 nt Target: 5′-GUGAAUUACAUCUUCUUUAAA-3′ (SEQ ID NO: 2696)AAT-913 21 nt Target: 5′-UGAAUUACAUCUUCUUUAAAG-3′ (SEQ ID NO: 2697)AAT-914 21 nt Target: 5′-GAAUUACAUCUUCUUUAAAGG-3′ (SEQ ID NO: 2698)AAT-915 21 nt Target: 5′-AAUUACAUCUUCUUUAAAGGC-3′ (SEQ ID NO: 2699)AAT-916 21 nt Target: 5′-AUUACAUCUUCUUUAAAGGCA-3′ (SEQ ID NO: 2700)AAT-917 21 nt Target: 5′-UUACAUCUUCUUUAAAGGCAA-3′ (SEQ ID NO: 2701)AAT-918 21 nt Target: 5′-UACAUCUUCUUUAAAGGCAAA-3′ (SEQ ID NO: 2702)AAT-922 21 nt Target: 5′-UCUUCUUUAAAGGCAAAUGGG-3′ (SEQ ID NO: 2703)AAT-924 21 nt Target: 5′-UUCUUUAAAGGCAAAUGGGAG-3′ (SEQ ID NO: 2704)AAT-932 21 nt Target: 5′-AGGCAAAUGGGAGAGACCCUU-3′ (SEQ ID NO: 2705)AAT-933 21 nt Target: 5′-GGCAAAUGGGAGAGACCCUUU-3′ (SEQ ID NO: 2706)AAT-934 21 nt Target: 5′-GCAAAUGGGAGAGACCCUUUG-3′ (SEQ ID NO: 2707)AAT-935 21 nt Target: 5′-CAAAUGGGAGAGACCCUUUGA-3′ (SEQ ID NO: 2708)AAT-1061 21 nt Target: 5′-GCUGUCCAGCUGGGUGCUGCU-3′ (SEQ ID NO: 2709)AAT-1062 21 nt Target: 5′-CUGUCCAGCUGGGUGCUGCUG-3′ (SEQ ID NO: 2710)AAT-1063 21 nt Target: 5′-UGUCCAGCUGGGUGCUGCUGA-3′ (SEQ ID NO: 2711)AAT-1064 21 nt Target: 5′-GUCCAGCUGGGUGCUGCUGAU-3′ (SEQ ID NO: 2712)AAT-1065 21 nt Target: 5′-UCCAGCUGGGUGCUGCUGAUG-3′ (SEQ ID NO: 2713)AAT-1066 21 nt Target: 5′-CCAGCUGGGUGCUGCUGAUGA-3′ (SEQ ID NO: 2714)AAT-1067 21 nt Target: 5′-CAGCUGGGUGCUGCUGAUGAA-3′ (SEQ ID NO: 2715)AAT-1068 21 nt Target: 5′-AGCUGGGUGCUGCUGAUGAAA-3′ (SEQ ID NO: 2716)AAT-1069 21 nt Target: 5′-GCUGGGUGCUGCUGAUGAAAU-3′ (SEQ ID NO: 2717)AAT-1070 21 nt Target: 5′-CUGGGUGCUGCUGAUGAAAUA-3′ (SEQ ID NO: 2718)AAT-1072 21 nt Target: 5′-GGGUGCUGCUGAUGAAAUACC-3′ (SEQ ID NO: 2719)AAT-1073 21 nt Target: 5′-GGUGCUGCUGAUGAAAUACCU-3′ (SEQ ID NO: 2720)AAT-1074 21 nt Target: 5′-GUGCUGCUGAUGAAAUACCUG-3′ (SEQ ID NO: 2721)AAT-1075 21 nt Target: 5′-UGCUGCUGAUGAAAUACCUGG-3′ (SEQ ID NO: 2722)AAT-1076 21 nt Target: 5′-GCUGCUGAUGAAAUACCUGGG-3′ (SEQ ID NO: 2723)AAT-1077 21 nt Target: 5′-CUGCUGAUGAAAUACCUGGGC-3′ (SEQ ID NO: 2724)AAT-1078 21 nt Target: 5′-UGCUGAUGAAAUACCUGGGCA-3′ (SEQ ID NO: 2725)AAT-1079 21 nt Target: 5′-GCUGAUGAAAUACCUGGGCAA-3′ (SEQ ID NO: 2726)AAT-1080 21 nt Target: 5′-CUGAUGAAAUACCUGGGCAAU-3′ (SEQ ID NO: 2727)AAT-1081 21 nt Target: 5′-UGAUGAAAUACCUGGGCAAUG-3′ (SEQ ID NO: 2728)AAT-1083 21 nt Target: 5′-AUGAAAUACCUGGGCAAUGCC-3′ (SEQ ID NO: 2729)AAT-1138 21 nt Target: 5′-UACAGCACCUGGAAAAUGAAC-3′ (SEQ ID NO: 2730)AAT-1144 21 nt Target: 5′-ACCUGGAAAAUGAACUCACCC-3′ (SEQ ID NO: 2731)AAT-1145 21 nt Target: 5′-CCUGGAAAAUGAACUCACCCA-3′ (SEQ ID NO: 2732)AAT-1165 21 nt Target: 5′-ACGAUAUCAUCACCAAGUUCC-3′ (SEQ ID NO: 2733)AAT-1176 21 nt Target: 5′-ACCAAGUUCCUGGAAAAUGAA-3′ (SEQ ID NO: 2734)AAT-1232 21 nt Target: 5′-GUCCAUUACUGGAACCUAUGA-3′ (SEQ ID NO: 2735)AAT-1233 21 nt Target: 5′-UCCAUUACUGGAACCUAUGAU-3′ (SEQ ID NO: 2736)AAT-1234 21 nt Target: 5′-CCAUUACUGGAACCUAUGAUC-3′ (SEQ ID NO: 2737)AAT-1235 21 nt Target: 5′-CAUUACUGGAACCUAUGAUCU-3′ (SEQ ID NO: 2738)AAT-1236 21 nt Target: 5′-AUUACUGGAACCUAUGAUCUG-3′ (SEQ ID NO: 2739)AAT-1237 21 nt Target: 5′-UUACUGGAACCUAUGAUCUGA-3′ (SEQ ID NO: 2740)AAT-1238 21 nt Target: 5′-UACUGGAACCUAUGAUCUGAA-3′ (SEQ ID NO: 2741)AAT-1239 21 nt Target: 5′-ACUGGAACCUAUGAUCUGAAG-3′ (SEQ ID NO: 2742)AAT-1240 21 nt Target: 5′-CUGGAACCUAUGAUCUGAAGA-3′ (SEQ ID NO: 2743)AAT-1279 21 nt Target: 5′-GCAUCACUAAGGUCUUCAGCA-3′ (SEQ ID NO: 2744)AAT-1280 21 nt Target: 5′-CAUCACUAAGGUCUUCAGCAA-3′ (SEQ ID NO: 2745)AAT-1281 21 nt Target: 5′-AUCACUAAGGUCUUCAGCAAU-3′ (SEQ ID NO: 2746)AAT-1283 21 nt Target: 5′-CACUAAGGUCUUCAGCAAUGG-3′ (SEQ ID NO: 2747)AAT-1284 21 nt Target: 5′-ACUAAGGUCUUCAGCAAUGGG-3′ (SEQ ID NO: 2748)AAT-1337 21 nt Target: 5′-CCUGAAGCUCUCCAAGGCCGU-3′ (SEQ ID NO: 2749)AAT-1338 21 nt Target: 5′-CUGAAGCUCUCCAAGGCCGUG-3′ (SEQ ID NO: 2750)AAT-1339 21 nt Target: 5′-UGAAGCUCUCCAAGGCCGUGC-3′ (SEQ ID NO: 2751)AAT-1442 21 nt Target: 5′-CCCCGAGGUCAAGUUCAACAA-3′ (SEQ ID NO: 2752)AAT-1443 21 nt Target: 5′-CCCGAGGUCAAGUUCAACAAA-3′ (SEQ ID NO: 2753)AAT-1444 21 nt Target: 5′-CCGAGGUCAAGUUCAACAAAC-3′ (SEQ ID NO: 2754)AAT-1445 21 nt Target: 5′-CGAGGUCAAGUUCAACAAACC-3′ (SEQ ID NO: 2755)AAT-1446 21 nt Target: 5′-GAGGUCAAGUUCAACAAACCC-3′ (SEQ ID NO: 2756)AAT-1447 21 nt Target: 5′-AGGUCAAGUUCAACAAACCCU-3′ (SEQ ID NO: 2757)AAT-1448 21 nt Target: 5′-GGUCAAGUUCAACAAACCCUU-3′ (SEQ ID NO: 2758)AAT-1449 21 nt Target: 5′-GUCAAGUUCAACAAACCCUUU-3′ (SEQ ID NO: 2759)AAT-1450 21 nt Target: 5′-UCAAGUUCAACAAACCCUUUG-3′ (SEQ ID NO: 2760)AAT-1451 21 nt Target: 5′-CAAGUUCAACAAACCCUUUGU-3′ (SEQ ID NO: 2761)

TABLE 15 Further Human Anti-α-1 antitrypsin “Blunt/Blunt” DsiRNAs5′-CCCCAGGGAGAUGCUGCCCAGAAGACA-3′ (SEQ ID NO: 2762)3′-GGGGUCCCUCUACGACGGGUCUUCUGU-5′ (SEQ ID NO: 2202)AAT-366 Target: 5′-CCCCAGGGAGATGCTGCCCAGAAGACA-3′ (SEQ ID NO: 2342)5′-CCCAGGGAGAUGCUGCCCAGAAGACAG-3′ (SEQ ID NO: 2763)3′-GGGUCCCUCUACGACGGGUCUUCUGUC-5′ (SEQ ID NO: 2203)AAT-367 Target: 5′-CCCAGGGAGATGCTGCCCAGAAGACAG-3′ (SEQ ID NO: 2343)5′-CCAGGGAGAUGCUGCCCAGAAGACAGA-3′ (SEQ ID NO: 2764)3′-GGUCCCUCUACGACGGGUCUUCUGUCU-5′ (SEQ ID NO: 2204)AAT-368 Target: 5′-CCAGGGAGATGCTGCCCAGAAGACAGA-3′ (SEQ ID NO: 2344)5′-CAGGGAGAUGCUGCCCAGAAGACAGAU-3′ (SEQ ID NO: 2765)3′-GUCCCUCUACGACGGGUCUUCUGUCUA-5′ (SEQ ID NO: 2205)AAT-369 Target: 5′-CAGGGAGATGCTGCCCAGAAGACAGAT-3′ (SEQ ID NO: 2345)5′-AGGGAGAUGCUGCCCAGAAGACAGAUA-3′ (SEQ ID NO: 2766)3′-UCCCUCUACGACGGGUCUUCUGUCUAU-5′ (SEQ ID NO: 2206)AAT-370 Target: 5′-AGGGAGATGCTGCCCAGAAGACAGATA-3′ (SEQ ID NO: 2346)5′-GGGAGAUGCUGCCCAGAAGACAGAUAC-3′ (SEQ ID NO: 2767)3′-CCCUCUACGACGGGUCUUCUGUCUAUG-5′ (SEQ ID NO: 2207)AAT-371 Target: 5′-GGGAGATGCTGCCCAGAAGACAGATAC-3′ (SEQ ID NO: 2347)5′-CAGAUACAUCCCACCAUGAUCAGGAUC-3′ (SEQ ID NO: 2768)3′-GUCUAUGUAGGGUGGUACUAGUCCUAG-5′ (SEQ ID NO: 2208)AAT-391 Target: 5′-CAGATACATCCCACCATGATCAGGATC-3′ (SEQ ID NO: 2348)5′-AGAUACAUCCCACCAUGAUCAGGAUCA-3′ (SEQ ID NO: 2769)3′-UCUAUGUAGGGUGGUACUAGUCCUAGU-5′ (SEQ ID NO: 2209)AAT-392 Target: 5′-AGATACATCCCACCATGATCAGGATCA-3′ (SEQ ID NO: 2349)5′-GAUACAUCCCACCAUGAUCAGGAUCAC-3′ (SEQ ID NO: 2770)3′-CUAUGUAGGGUGGUACUAGUCCUAGUG-5′ (SEQ ID NO: 2210)AAT-393 Target: 5′-GATACATCCCACCATGATCAGGATCAC-3′ (SEQ ID NO: 2350)5′-AUACAUCCCACCAUGAUCAGGAUCACC-3′ (SEQ ID NO: 2771)3′-UAUGUAGGGUGGUACUAGUCCUAGUGG-5′ (SEQ ID NO: 2211)AAT-394 Target: 5′-ATACATCCCACCATGATCAGGATCACC-3′ (SEQ ID NO: 2351)5′-ACACCAGUCCAACAGCACCAAUAUCUU-3′ (SEQ ID NO: 2772)3′-UGUGGUCAGGUUGUCGUGGUUAUAGAA-5′ (SEQ ID NO: 2212)AAT-485 Target: 5′-ACACCAGTCCAACAGCACCAATATCTT-3′ (SEQ ID NO: 2352)5′-CACCAGUCCAACAGCACCAAUAUCUUC-3′ (SEQ ID NO: 2773)3′-GUGGUCAGGUUGUCGUGGUUAUAGAAG-5′ (SEQ ID NO: 2213)AAT-486 Target: 5′-CACCAGTCCAACAGCACCAATATCTTC-3′ (SEQ ID NO: 2353)5′-ACCAGUCCAACAGCACCAAUAUCUUCU-3′ (SEQ ID NO: 2774)3′-UGGUCAGGUUGUCGUGGUUAUAGAAGA-5′ (SEQ ID NO: 2214)AAT-487 Target: 5′-ACCAGTCCAACAGCACCAATATCTTCT-3′ (SEQ ID NO: 2354)5′-CCAGUCCAACAGCACCAAUAUCUUCUU-3′ (SEQ ID NO: 2775)3′-GGUCAGGUUGUCGUGGUUAUAGAAGAA-5′ (SEQ ID NO: 2215)AAT-488 Target: 5′-CCAGTCCAACAGCACCAATATCTTCTT-3′ (SEQ ID NO: 2355)5′-CAGUCCAACAGCACCAAUAUCUUCUUC-3′ (SEQ ID NO: 2776)3′-GUCAGGUUGUCGUGGUUAUAGAAGAAG-5′ (SEQ ID NO: 2216)AAT-489 Target: 5′-CAGTCCAACAGCACCAATATCTTCTTC-3′ (SEQ ID NO: 2356)5′-AGUCCAACAGCACCAAUAUCUUCUUCU-3′ (SEQ ID NO: 2777)3′-UCAGGUUGUCGUGGUUAUAGAAGAAGA-5′ (SEQ ID NO: 2217)AAT-490 Target: 5′-AGTCCAACAGCACCAATATCTTCTTCT-3′ (SEQ ID NO: 2357)5′-GUCCAACAGCACCAAUAUCUUCUUCUC-3′ (SEQ ID NO: 277 8)3′-CAGGUUGUCGUGGUUAUAGAAGAAGAG-5′ (SEQ ID NO: 2218)AAT-491 Target: 5′-GTCCAACAGCACCAATATCTTCTTCTC-3′ (SEQ ID NO: 2358)5′-UCCAACAGCACCAAUAUCUUCUUCUCC-3′ (SEQ ID NO: 2779)3′-AGGUUGUCGUGGUUAUAGAAGAAGAGG-5′ (SEQ ID NO: 2219)AAT-492 Target: 5′-TCCAACAGCACCAATATCTTCTTCTCC-3′ (SEQ ID NO: 2359)5′-CCAACAGCACCAAUAUCUUCUUCUCCC-3′ (SEQ ID NO: 2780)3′-GGUUGUCGUGGUUAUAGAAGAAGAGGG-5′ (SEQ ID NO: 2220)AAT-493 Target: 5′-CCAACAGCACCAATATCTTCTTCTCCC-3′ (SEQ ID NO: 2360)5′-CAACAGCACCAAUAUCUUCUUCUCCCC-3′ (SEQ ID NO: 2781)3′-GUUGUCGUGGUUAUAGAAGAAGAGGGG-5′ (SEQ ID NO: 2221)AAT-494 Target: 5′-CAACAGCACCAATATCTTCTTCTCCCC-3′ (SEQ ID NO: 2361)5′-AACAGCACCAAUAUCUUCUUCUCCCCA-3′ (SEQ ID NO: 2782)3′-UUGUCGUGGUUAUAGAAGAAGAGGGGU-5′ (SEQ ID NO: 2222)AAT-495 Target: 5′-AACAGCACCAATATCTTCTTCTCCCCA-3′ (SEQ ID NO: 2362)5′-ACAGCACCAAUAUCUUCUUCUCCCCAG-3′ (SEQ ID NO: 2783)3′-UGUCGUGGUUAUAGAAGAAGAGGGGUC-5′ (SEQ ID NO: 2223)AAT-496 Target: 5′-ACAGCACCAATATCTTCTTCTCCCCAG-3′ (SEQ ID NO: 2363)5′-CAGCACCAAUAUCUUCUUCUCCCCAGU-3′ (SEQ ID NO: 2784)3′-GUCGUGGUUAUAGAAGAAGAGGGGUCA-5′ (SEQ ID NO: 2224)AAT-497 Target: 5′-CAGCACCAATATCTTCTTCTCCCCAGT-3′ (SEQ ID NO: 2364)5′-AGCACCAAUAUCUUCUUCUCCCCAGUG-3′ (SEQ ID NO: 2785)3′-UCGUGGUUAUAGAAGAAGAGGGGUCAC-5′ (SEQ ID NO: 2225)AAT-498 Target: 5′-AGCACCAATATCTTCTTCTCCCCAGTG-3′ (SEQ ID NO: 2365)5′-GCACCAAUAUCUUCUUCUCCCCAGUGA-3′ (SEQ ID NO: 2786)3′-CGUGGUUAUAGAAGAAGAGGGGUCACU-5′ (SEQ ID NO: 2226)AAT-499 Target: 5′-GCACCAATATCTTCTTCTCCCCAGTGA-3′ (SEQ ID NO: 2366)5′-UCCCCAGUGAGCAUCGCUACAGCCUUU-3′ (SEQ ID NO: 2787)3′-AGGGGUCACUCGUAGCGAUGUCGGAAA-5′ (SEQ ID NO: 2227)AAT-516 Target: 5′-TCCCCAGTGAGCATCGCTACAGCCTTT-3′ (SEQ ID NO: 2367)5′-CCCCAGUGAGCAUCGCUACAGCCUUUG-3′ (SEQ ID NO: 2788)3′-GGGGUCACUCGUAGCGAUGUCGGAAAC-5′ (SEQ ID NO: 2228)AAT-517 Target: 5′-CCCCAGTGAGCATCGCTACAGCCTTTG-3′ (SEQ ID NO: 2368)5′-CCCAGUGAGCAUCGCUACAGCCUUUGC-3′ (SEQ ID NO: 2789)3′-GGGUCACUCGUAGCGAUGUCGGAAACG-5′ (SEQ ID NO: 2229)AAT-518 Target: 5′-CCCAGTGAGCATCGCTACAGCCTTTGC-3′ (SEQ ID NO: 2369)5′-CCAGUGAGCAUCGCUACAGCCUUUGCA-3′ (SEQ ID NO: 2790)3′-GGUCACUCGUAGCGAUGUCGGAAACGU-5′ (SEQ ID NO: 2230)AAT-519 Target: 5′-CCAGTGAGCATCGCTACAGCCTTTGCA-3′ (SEQ ID NO: 2370)5′-CAGUGAGCAUCGCUACAGCCUUUGCAA-3′ (SEQ ID NO: 2791)3′-GUCACUCGUAGCGAUGUCGGAAACGUU-5′ (SEQ ID NO: 2231)AAT-520 Target: 5′-CAGTGAGCATCGCTACAGCCTTTGCAA-3′ (SEQ ID NO: 2371)5′-AGUGAGCAUCGCUACAGCCUUUGCAAU-3′ (SEQ ID NO: 2792)3′-UCACUCGUAGCGAUGUCGGAAACGUUA-5′ (SEQ ID NO: 2232)AAT-521 Target: 5′-AGTGAGCATCGCTACAGCCTTTGCAAT-3′ (SEQ ID NO: 2372)5′-GUGAGCAUCGCUACAGCCUUUGCAAUG-3′ (SEQ ID NO: 2793)3′-CACUCGUAGCGAUGUCGGAAACGUUAC-5′ (SEQ ID NO: 2233)AAT-522 Target: 5′-GTGAGCATCGCTACAGCCTTTGCAATG-3′ (SEQ ID NO: 2373)5′-UGAGCAUCGCUACAGCCUUUGCAAUGC-3′ (SEQ ID NO: 2794)3′-ACUCGUAGCGAUGUCGGAAACGUUACG-5′ (SEQ ID NO: 2234)AAT-523 Target: 5′-TGAGCATCGCTACAGCCTTTGCAATGC-3′ (SEQ ID NO: 2374)5′-GAGCAUCGCUACAGCCUUUGCAAUGCU-3′ (SEQ ID NO: 2795)3′-CUCGUAGCGAUGUCGGAAACGUUACGA-5′ (SEQ ID NO: 2235)AAT-524 Target: 5′-GAGCATCGCTACAGCCTTTGCAATGCT-3′ (SEQ ID NO: 2375)5′-AGCAUCGCUACAGCCUUUGCAAUGCUC-3′ (SEQ ID NO: 2796)3′-UCGUAGCGAUGUCGGAAACGUUACGAG-5′ (SEQ ID NO: 2236)AAT-525 Target: 5′-AGCATCGCTACAGCCTTTGCAATGCTC-3′ (SEQ ID NO: 2376)5′-GCAUCGCUACAGCCUUUGCAAUGCUCU-3′ (SEQ ID NO: 2797)3′-CGUAGCGAUGUCGGAAACGUUACGAGA-5′ (SEQ ID NO: 2237)AAT-526 Target: 5′-GCATCGCTACAGCCTTTGCAATGCTCT-3′ (SEQ ID NO: 2377)5′-CAUCGCUACAGCCUUUGCAAUGCUCUC-3′ (SEQ ID NO: 2798)3′-GUAGCGAUGUCGGAAACGUUACGAGAG-5′ (SEQ ID NO: 2238)AAT-527 Target: 5′-CATCGCTACAGCCTTTGCAATGCTCTC-3′ (SEQ ID NO: 2378)5′-AUCGCUACAGCCUUUGCAAUGCUCUCC-3′ (SEQ ID NO: 2799)3′-UAGCGAUGUCGGAAACGUUACGAGAGG-5′ (SEQ ID NO: 2239)AAT-528 Target: 5′-ATCGCTACAGCCTTTGCAATGCTCTCC-3′ (SEQ ID NO: 2379)5′-UCGCUACAGCCUUUGCAAUGCUCUCCC-3′ (SEQ ID NO: 2800)3′-AGCGAUGUCGGAAACGUUACGAGAGGG-5′ (SEQ ID NO: 2240)AAT-529 Target: 5′-TCGCTACAGCCTTTGCAATGCTCTCCC-3′ (SEQ ID NO: 2380)5′-CGCUACAGCCUUUGCAAUGCUCUCCCU-3′ (SEQ ID NO: 2801)3′-GCGAUGUCGGAAACGUUACGAGAGGGA-5′ (SEQ ID NO: 2241)AAT-530 Target: 5′-CGCTACAGCCTTTGCAATGCTCTCCCT-3′ (SEQ ID NO: 2381)5′-GCUACAGCCUUUGCAAUGCUCUCCCUG-3′ (SEQ ID NO: 2802)3′-CGAUGUCGGAAACGUUACGAGAGGGAC-5′ (SEQ ID NO: 2242)AAT-531 Target: 5′-GCTACAGCCTTTGCAATGCTCTCCCTG-3′ (SEQ ID NO: 2382)5′-UCCCUGGGGACCAAGGCUGACACUCAC-3′ (SEQ ID NO: 2803)3′-AGGGACCCCUGGUUCCGACUGUGAGUG-5′ (SEQ ID NO: 2243)AAT-552 Target: 5′-TCCCTGGGGACCAAGGCTGACACTCAC-3′ (SEQ ID NO: 2383)5′-UGGGGACCAAGGCUGACACUCACGAUG-3′ (SEQ ID NO: 2804)3′-ACCCCUGGUUCCGACUGUGAGUGCUAC-5′ (SEQ ID NO: 2244)AAT-556 Target: 5′-TGGGGACCAAGGCTGACACTCACGATG-3′ (SEQ ID NO: 2384)5′-GGGGACCAAGGCUGACACUCACGAUGA-3′ (SEQ ID NO: 2805)3′-CCCCUGGUUCCGACUGUGAGUGCUACU-5′ (SEQ ID NO: 2245)AAT-557 Target: 5′-GGGGACCAAGGCTGACACTCACGATGA-3′ (SEQ ID NO: 2385)5′-GGGACCAAGGCUGACACUCACGAUGAA-3′ (SEQ ID NO: 2806)3′-CCCUGGUUCCGACUGUGAGUGCUACUU-5′ (SEQ ID NO: 2246)AAT-558 Target: 5′-GGGACCAAGGCTGACACTCACGATGAA-3′ (SEQ ID NO: 2386)5′-GAUGAAAUCCUGGAGGGCCUGAAUUUC-3′ (SEQ ID NO: 2807)3′-CUACUUUAGGACCUCCCGGACUUAAAG-5′ (SEQ ID NO: 2247)AAT-579 Target: 5′-GATGAAATCCTGGAGGGCCTGAATTTC-3′ (SEQ ID NO: 2387)5′-AUGAAAUCCUGGAGGGCCUGAAUUUCA-3′ (SEQ ID NO: 2808)3′-UACUUUAGGACCUCCCGGACUUAAAGU-5′ (SEQ ID NO: 2248)AAT-580 Target: 5′-ATGAAATCCTGGAGGGCCTGAATTTCA-3′ (SEQ ID NO: 2388)5′-GAUCCAUGAAGGCUUCCAGGAACUCCU-3′ (SEQ ID NO: 2809)3′-CUAGGUACUUCCGAAGGUCCUUGAGGA-5′ (SEQ ID NO: 2249)AAT-632 Target: 5′-GATCCATGAAGGCTTCCAGGAACTCCT-3′ (SEQ ID NO: 2389)5′-AUCCAUGAAGGCUUCCAGGAACUCCUC-3′ (SEQ ID NO: 2810)3′-UAGGUACUUCCGAAGGUCCUUGAGGAG-5′ (SEQ ID NO: 2250)AAT-633 Target: 5′-ATCCATGAAGGCTTCCAGGAACTCCTC-3′ (SEQ ID NO: 2390)5′-GGGGACACCGAAGAGGCCAAGAAACAG-3′ (SEQ ID NO: 2811)3′-CCCCUGUGGCUUCUCCGGUUCUUUGUC-5′ (SEQ ID NO: 2251)AAT-801 Target: 5′-GGGGACACCGAAGAGGCCAAGAAACAG-3′ (SEQ ID NO: 2391)5′-GGGACACCGAAGAGGCCAAGAAACAGA-3′ (SEQ ID NO: 2812)3′-CCCUGUGGCUUCUCCGGUUCUUUGUCU-5′ (SEQ ID NO: 2252)AAT-802 Target: 5′-GGGACACCGAAGAGGCCAAGAAACAGA-3′ (SEQ ID NO: 2392)5′-GGACACCGAAGAGGCCAAGAAACAGAU-3′ (SEQ ID NO: 2813)3′-CCUGUGGCUUCUCCGGUUCUUUGUCUA-5′ (SEQ ID NO: 2253)AAT-803 Target: 5′-GGACACCGAAGAGGCCAAGAAACAGAT-3′ (SEQ ID NO: 2393)5′-GACACCGAAGAGGCCAAGAAACAGAUC-3′ (SEQ ID NO: 2814)3′-CUGUGGCUUCUCCGGUUCUUUGUCUAG-5′ (SEQ ID NO: 2254)AAT-804 Target: 5′-GACACCGAAGAGGCCAAGAAACAGATC-3′ (SEQ ID NO: 2394)5′-ACACCGAAGAGGCCAAGAAACAGAUCA-3′ (SEQ ID NO: 2815)3′-UGUGGCUUCUCCGGUUCUUUGUCUAGU-5′ (SEQ ID NO: 2255)AAT-805 Target: 5′-ACACCGAAGAGGCCAAGAAACAGATCA-3′ (SEQ ID NO: 2395)5′-CACCGAAGAGGCCAAGAAACAGAUCAA-3′ (SEQ ID NO: 2816)3′-GUGGCUUCUCCGGUUCUUUGUCUAGUU-5′ (SEQ ID NO: 2256)AAT-806 Target: 5′-CACCGAAGAGGCCAAGAAACAGATCAA-3′ (SEQ ID NO: 2396)5′-ACCGAAGAGGCCAAGAAACAGAUCAAC-3′ (SEQ ID NO: 2817)3′-UGGCUUCUCCGGUUCUUUGUCUAGUUG-5′ (SEQ ID NO: 2257)AAT-807 Target: 5′-ACCGAAGAGGCCAAGAAACAGATCAAC-3′ (SEQ ID NO: 2397)5′-CCGAAGAGGCCAAGAAACAGAUCAACG-3′ (SEQ ID NO: 2818)3′-GGCUUCUCCGGUUCUUUGUCUAGUUGC-5′ (SEQ ID NO: 2258)AAT-808 Target: 5′-CCGAAGAGGCCAAGAAACAGATCAACG-3′ (SEQ ID NO: 2398)5′-CGAAGAGGCCAAGAAACAGAUCAACGA-3′ (SEQ ID NO: 2819)3′-GCUUCUCCGGUUCUUUGUCUAGUUGCU-5′ (SEQ ID NO: 2259)AAT-809 Target: 5′-CGAAGAGGCCAAGAAACAGATCAACGA-3′ (SEQ ID NO: 2399)5′-GAAGAGGCCAAGAAACAGAUCAACGAU-3′ (SEQ ID NO: 2820)3′-CUUCUCCGGUUCUUUGUCUAGUUGCUA-5′ (SEQ ID NO: 2260)AAT-810 Target: 5′-GAAGAGGCCAAGAAACAGATCAACGAT-3′ (SEQ ID NO: 2400)5′-AAGAGGCCAAGAAACAGAUCAACGAUU-3′ (SEQ ID NO: 2821)3′-UUCUCCGGUUCUUUGUCUAGUUGCUAA-5′ (SEQ ID NO: 2261)AAT-811 Target: 5′-AAGAGGCCAAGAAACAGATCAACGATT-3′ (SEQ ID NO: 2401)5′-AGAGGCCAAGAAACAGAUCAACGAUUA-3′ (SEQ ID NO: 2822)3′-UCUCCGGUUCUUUGUCUAGUUGCUAAU-5′ (SEQ ID NO: 2262)AAT-812 Target: 5′-AGAGGCCAAGAAACAGATCAACGATTA-3′ (SEQ ID NO: 2402)5′-GAGGCCAAGAAACAGAUCAACGAUUAC-3′ (SEQ ID NO: 2823)3′-CUCCGGUUCUUUGUCUAGUUGCUAAUG-5′ (SEQ ID NO: 2263)AAT-813 Target: 5′-GAGGCCAAGAAACAGATCAACGATTAC-3′ (SEQ ID NO: 2403)5′-GUUUUUGCUCUGGUGAAUUACAUCUUC-3′ (SEQ ID NO: 2824)3′-CAAAAACGAGACCACUUAAUGUAGAAG-5′ (SEQ ID NO: 2264)AAT-900 Target: 5′-GTTTTTGCTCTGGTGAATTACATCTTC-3′ (SEQ ID NO: 2404)5′-UUUUUGCUCUGGUGAAUUACAUCUUCU-3′ (SEQ ID NO: 2825)3′-AAAAACGAGACCACUUAAUGUAGAAGA-5′ (SEQ ID NO: 2265)AAT-901 Target: 5′-TTTTTGCTCTGGTGAATTACATCTTCT-3′ (SEQ ID NO: 2405)5′-UUUUGCUCUGGUGAAUUACAUCUUCUU-3′ (SEQ ID NO: 2826)3′-AAAACGAGACCACUUAAUGUAGAAGAA-5′ (SEQ ID NO: 2266)AAT-902 Target: 5′-TTTTGCTCTGGTGAATTACATCTTCTT-3′ (SEQ ID NO: 2406)5′-UUUGCUCUGGUGAAUUACAUCUUCUUU-3′ (SEQ ID NO: 2827)3′-AAACGAGACCACUUAAUGUAGAAGAAA-5′ (SEQ ID NO: 2267)AAT-903 Target: 5′-TTTGCTCTGGTGAATTACATCTTCTTT-3′ (SEQ ID NO: 2407)5′-UUGCUCUGGUGAAUUACAUCUUCUUUA-3′ (SEQ ID NO: 2828)3′-AACGAGACCACUUAAUGUAGAAGAAAU-5′ (SEQ ID NO: 2268)AAT-904 Target: 5′-TTGCTCTGGTGAATTACATCTTCTTTA-3′ (SEQ ID NO: 2408)5′-UGCUCUGGUGAAUUACAUCUUCUUUAA-3′ (SEQ ID NO: 2829)3′-ACGAGACCACUUAAUGUAGAAGAAAUU-5′ (SEQ ID NO: 2269)AAT-905 Target: 5′-TGCTCTGGTGAATTACATCTTCTTTAA-3′ (SEQ ID NO: 2409)5′-GCUCUGGUGAAUUACAUCUUCUUUAAA-3′ (SEQ ID NO: 2830)3′-CGAGACCACUUAAUGUAGAAGAAAUUU-5′ (SEQ ID NO: 2270)AAT-906 Target: 5′-GCTCTGGTGAATTACATCTTCTTTAAA-3′ (SEQ ID NO: 2410)5′-CUCUGGUGAAUUACAUCUUCUUUAAAG-3′ (SEQ ID NO: 2831)3′-GAGACCACUUAAUGUAGAAGAAAUUUC-5′ (SEQ ID NO: 2271)AAT-907 Target: 5′-CTCTGGTGAATTACATCTTCTTTAAAG-3′ (SEQ ID NO: 2411)5′-UCUGGUGAAUUACAUCUUCUUUAAAGG-3′ (SEQ ID NO: 2832)3′-AGACCACUUAAUGUAGAAGAAAUUUCC-5′ (SEQ ID NO: 2272)AAT-908 Target: 5′-TCTGGTGAATTACATCTTCTTTAAAGG-3′ (SEQ ID NO: 2412)5′-CUGGUGAAUUACAUCUUCUUUAAAGGC-3′ (SEQ ID NO: 2833)3′-GACCACUUAAUGUAGAAGAAAUUUCCG-5′ (SEQ ID NO: 2273)AAT-909 Target: 5′-CTGGTGAATTACATCTTCTTTAAAGGC-3′ (SEQ ID NO: 2413)5′-UGGUGAAUUACAUCUUCUUUAAAGGCA-3′ (SEQ ID NO: 2834)3′-ACCACUUAAUGUAGAAGAAAUUUCCGU-5′ (SEQ ID NO: 2274)AAT-910 Target: 5′-TGGTGAATTACATCTTCTTTAAAGGCA-3′ (SEQ ID NO: 2414)5′-GGUGAAUUACAUCUUCUUUAAAGGCAA-3′ (SEQ ID NO: 2835)3′-CCACUUAAUGUAGAAGAAAUUUCCGUU-5′ (SEQ ID NO: 2275)AAT-911 Target: 5′-GGTGAATTACATCTTCTTTAAAGGCAA-3′ (SEQ ID NO: 2415)5′-GUGAAUUACAUCUUCUUUAAAGGCAAA-3′ (SEQ ID NO: 2836)3′-CACUUAAUGUAGAAGAAAUUUCCGUUU-5′ (SEQ ID NO: 2276)AAT-912 Target: 5′-GTGAATTACATCTTCTTTAAAGGCAAA-3′ (SEQ ID NO: 2416)5′-UGAAUUACAUCUUCUUUAAAGGCAAAU-3′ (SEQ ID NO: 2837)3′-ACUUAAUGUAGAAGAAAUUUCCGUUUA-5′ (SEQ ID NO: 2277)AAT-913 Target: 5′-TGAATTACATCTTCTTTAAAGGCAAAT-3′ (SEQ ID NO: 2417)5′-GAAUUACAUCUUCUUUAAAGGCAAAUG-3′ (SEQ ID NO: 2838)3′-CUUAAUGUAGAAGAAAUUUCCGUUUAC-5′ (SEQ ID NO: 2278)AAT-914 Target: 5′-GAATTACATCTTCTTTAAAGGCAAATG-3′ (SEQ ID NO: 2418)5′-AAUUACAUCUUCUUUAAAGGCAAAUGG-3′ (SEQ ID NO: 2839)3′-UUAAUGUAGAAGAAAUUUCCGUUUACC-5′ (SEQ ID NO: 2279)AAT-915 Target: 5′-AATTACATCTTCTTTAAAGGCAAATGG-3′ (SEQ ID NO: 2419)5′-AUUACAUCUUCUUUAAAGGCAAAUGGG-3′ (SEQ ID NO: 2840)3′-UAAUGUAGAAGAAAUUUCCGUUUACCC-5′ (SEQ ID NO: 2280)AAT-916 Target: 5′-ATTACATCTTCTTTAAAGGCAAATGGG-3′ (SEQ ID NO: 2420)5′-UUACAUCUUCUUUAAAGGCAAAUGGGA-3′ (SEQ ID NO: 2841)3′-AAUGUAGAAGAAAUUUCCGUUUACCCU-5′ (SEQ ID NO: 2281)AAT-917 Target: 5′-TTACATCTTCTTTAAAGGCAAATGGGA-3′ (SEQ ID NO: 2421)5′-UACAUCUUCUUUAAAGGCAAAUGGGAG-3′ (SEQ ID NO: 2842)3′-AUGUAGAAGAAAUUUCCGUUUACCCUC-5′ (SEQ ID NO: 2282)AAT-918 Target: 5′-TACATCTTCTTTAAAGGCAAATGGGAG-3′ (SEQ ID NO: 2422)5′-UCUUCUUUAAAGGCAAAUGGGAGAGAC-3′ (SEQ ID NO: 2843)3′-AGAAGAAAUUUCCGUUUACCCUCUCUG-5′ (SEQ ID NO: 2283)AAT-922 Target: 5′-TCTTCTTTAAAGGCAAATGGGAGAGAC-3′ (SEQ ID NO: 2423)5′-UUCUUUAAAGGCAAAUGGGAGAGACCC-3′ (SEQ ID NO: 2844)3′-AAGAAAUUUCCGUUUACCCUCUCUGGG-5′ (SEQ ID NO: 2284)AAT-924 Target: 5′-TTCTTTAAAGGCAAATGGGAGAGACCC-3′ (SEQ ID NO: 2424)5′-AGGCAAAUGGGAGAGACCCUUUGAAGU-3′ (SEQ ID NO: 2845)3′-UCCGUUUACCCUCUCUGGGAAACUUCA-5′ (SEQ ID NO: 2285)AAT-932 Target: 5′-AGGCAAATGGGAGAGACCCTTTGAAGT-3′ (SEQ ID NO: 2425)5′-GGCAAAUGGGAGAGACCCUUUGAAGUC-3′ (SEQ ID NO: 2846)3′-CCGUUUACCCUCUCUGGGAAACUUCAG-5′ (SEQ ID NO: 2286)AAT-933 Target: 5′-GGCAAATGGGAGAGACCCTTTGAAGTC-3′ (SEQ ID NO: 2426)5′-GCAAAUGGGAGAGACCCUUUGAAGUCA-3′ (SEQ ID NO: 2847)3′-CGUUUACCCUCUCUGGGAAACUUCAGU-5′ (SEQ ID NO: 2287)AAT-934 Target: 5′-GCAAATGGGAGAGACCCTTTGAAGTCA-3′ (SEQ ID NO: 2427)5′-CAAAUGGGAGAGACCCUUUGAAGUCAA-3′ (SEQ ID NO: 2848)3′-GUUUACCCUCUCUGGGAAACUUCAGUU-5′ (SEQ ID NO: 2288)AAT-935 Target: 5′-CAAATGGGAGAGACCCTTTGAAGTCAA-3′ (SEQ ID NO: 2428)5′-GCUGUCCAGCUGGGUGCUGCUGAUGAA-3′ (SEQ ID NO: 2849)3′-CGACAGGUCGACCCACGACGACUACUU-5′ (SEQ ID NO: 2289)AAT-1061 Target: 5′-GCTGTCCAGCTGGGTGCTGCTGATGAA-3′ (SEQ ID NO: 2429)5′-CUGUCCAGCUGGGUGCUGCUGAUGAAA-3′ (SEQ ID NO: 2850)3′-GACAGGUCGACCCACGACGACUACUUU-5′ (SEQ ID NO: 2290)AAT-1062 Target: 5′-CTGTCCAGCTGGGTGCTGCTGATGAAA-3′ (SEQ ID NO: 2430)5′-UGUCCAGCUGGGUGCUGCUGAUGAAAU-3′ (SEQ ID NO: 2851)3′-ACAGGUCGACCCACGACGACUACUUUA-5′ (SEQ ID NO: 2291)AAT-1063 Target: 5′-TGTCCAGCTGGGTGCTGCTGATGAAAT-3′ (SEQ ID NO: 2431)5′-GUCCAGCUGGGUGCUGCUGAUGAAAUA-3′ (SEQ ID NO: 2852)3′-CAGGUCGACCCACGACGACUACUUUAU-5′ (SEQ ID NO: 2292)AAT-1064 Target: 5′-GTCCAGCTGGGTGCTGCTGATGAAATA-3′ (SEQ ID NO: 2432)5′-UCCAGCUGGGUGCUGCUGAUGAAAUAC-3′ (SEQ ID NO: 2853)3′-AGGUCGACCCACGACGACUACUUUAUG-5′ (SEQ ID NO: 2293)AAT-1065 Target: 5′-TCCAGCTGGGTGCTGCTGATGAAATAC-3′ (SEQ ID NO: 2433)5′-CCAGCUGGGUGCUGCUGAUGAAAUACC-3′ (SEQ ID NO: 2854)3′-GGUCGACCCACGACGACUACUUUAUGG-5′ (SEQ ID NO: 2294)AAT-1066 Target: 5′-CCAGCTGGGTGCTGCTGATGAAATACC-3′ (SEQ ID NO: 2434)5′-CAGCUGGGUGCUGCUGAUGAAAUACCU-3′ (SEQ ID NO: 2855)3′-GUCGACCCACGACGACUACUUUAUGGA-5′ (SEQ ID NO: 2295)AAT-1067 Target: 5′-CAGCTGGGTGCTGCTGATGAAATACCT-3′ (SEQ ID NO: 2435)5′-AGCUGGGUGCUGCUGAUGAAAUACCUG-3′ (SEQ ID NO: 2856)3′-UCGACCCACGACGACUACUUUAUGGAC-5′ (SEQ ID NO: 2296)AAT-1068 Target: 5′-AGCTGGGTGCTGCTGATGAAATACCTG-3′ (SEQ ID NO: 2436)5′-GCUGGGUGCUGCUGAUGAAAUACCUGG-3′ (SEQ ID NO: 2857)3′-CGACCCACGACGACUACUUUAUGGACC-5′ (SEQ ID NO: 2297)AAT-1069 Target: 5′-GCTGGGTGCTGCTGATGAAATACCTGG-3′ (SEQ ID NO: 2437)5′-CUGGGUGCUGCUGAUGAAAUACCUGGG-3′ (SEQ ID NO: 2858)3′-GACCCACGACGACUACUUUAUGGACCC-5′ (SEQ ID NO: 2298)AAT-1070 Target: 5′-CTGGGTGCTGCTGATGAAATACCTGGG-3′ (SEQ ID NO: 2438)5′-GGGUGCUGCUGAUGAAAUACCUGGGCA-3′ (SEQ ID NO: 2859)3′-CCCACGACGACUACUUUAUGGACCCGU-5′ (SEQ ID NO: 2299)AAT-1072 Target: 5′-GGGTGCTGCTGATGAAATACCTGGGCA-3′ (SEQ ID NO: 2439)5′-GGUGCUGCUGAUGAAAUACCUGGGCAA-3′ (SEQ ID NO: 2860)3′-CCACGACGACUACUUUAUGGACCCGUU-5′ (SEQ ID NO: 2300)AAT-1073 Target: 5′-GGTGCTGCTGATGAAATACCTGGGCAA-3′ (SEQ ID NO: 2440)5′-GUGCUGCUGAUGAAAUACCUGGGCAAU-3′ (SEQ ID NO: 2861)3′-CACGACGACUACUUUAUGGACCCGUUA-5′ (SEQ ID NO: 2301)AAT-1074 Target: 5′-GTGCTGCTGATGAAATACCTGGGCAAT-3′ (SEQ ID NO: 2441)5′-UGCUGCUGAUGAAAUACCUGGGCAAUG-3′ (SEQ ID NO: 2862)3′-ACGACGACUACUUUAUGGACCCGUUAC-5′ (SEQ ID NO: 2302)AAT-1075 Target: 5′-TGCTGCTGATGAAATACCTGGGCAATG-3′ (SEQ ID NO: 2442)5′-GCUGCUGAUGAAAUACCUGGGCAAUGC-3′ (SEQ ID NO: 2863)3′-CGACGACUACUUUAUGGACCCGUUACG-5′ (SEQ ID NO: 2303)AAT-1076 Target: 5′-GCTGCTGATGAAATACCTGGGCAATGC-3′ (SEQ ID NO: 2443)5′-CUGCUGAUGAAAUACCUGGGCAAUGCC-3′ (SEQ ID NO: 2864)3′-GACGACUACUUUAUGGACCCGUUACGG-5′ (SEQ ID NO: 2304)AAT-1077 Target: 5′-CTGCTGATGAAATACCTGGGCAATGCC-3′ (SEQ ID NO: 2444)5′-UGCUGAUGAAAUACCUGGGCAAUGCCA-3′ (SEQ ID NO: 2865)3′-ACGACUACUUUAUGGACCCGUUACGGU-5′ (SEQ ID NO: 2305)AAT-1078 Target: 5′-TGCTGATGAAATACCTGGGCAATGCCA-3′ (SEQ ID NO: 2445)5′-GCUGAUGAAAUACCUGGGCAAUGCCAC-3′ (SEQ ID NO: 2866)3′-CGACUACUUUAUGGACCCGUUACGGUG-5′ (SEQ ID NO: 2306)AAT-1079 Target: 5′-GCTGATGAAATACCTGGGCAATGCCAC-3′ (SEQ ID NO: 2446)5′-CUGAUGAAAUACCUGGGCAAUGCCACC-3′ (SEQ ID NO: 2867)3′-GACUACUUUAUGGACCCGUUACGGUGG-5′ (SEQ ID NO: 2307)AAT-1080 Target: 5′-CTGATGAAATACCTGGGCAATGCCACC-3′ (SEQ ID NO: 2447)5′-UGAUGAAAUACCUGGGCAAUGCCACCG-3′ (SEQ ID NO: 2868)3′-ACUACUUUAUGGACCCGUUACGGUGGC-5′ (SEQ ID NO: 2308)AAT-1081 Target: 5′-TGATGAAATACCTGGGCAATGCCACCG-3′ (SEQ ID NO: 2448)5′-AUGAAAUACCUGGGCAAUGCCACCGCC-3′ (SEQ ID NO: 2869)3′-UACUUUAUGGACCCGUUACGGUGGCGG-5′ (SEQ ID NO: 2309)AAT-1083 Target: 5′-ATGAAATACCTGGGCAATGCCACCGCC-3′ (SEQ ID NO: 2449)5′-UACAGCACCUGGAAAAUGAACUCACCC-3′ (SEQ ID NO: 2870)3′-AUGUCGUGGACCUUUUACUUGAGUGGG-5′ (SEQ ID NO: 2310)AAT-1138 Target: 5′-TACAGCACCTGGAAAATGAACTCACCC-3′ (SEQ ID NO: 2450)5′-ACCUGGAAAAUGAACUCACCCACGAUA-3′ (SEQ ID NO: 2871)3′-UGGACCUUUUACUUGAGUGGGUGCUAU-5′ (SEQ ID NO: 2311)AAT-1144 Target: 5′-ACCTGGAAAATGAACTCACCCACGATA-3′ (SEQ ID NO: 2451)5′-CCUGGAAAAUGAACUCACCCACGAUAU-3′ (SEQ ID NO: 2872)3′-GGACCUUUUACUUGAGUGGGUGCUAUA-5′ (SEQ ID NO: 2312)AAT-1145 Target: 5′-CCTGGAAAATGAACTCACCCACGATAT-3′ (SEQ ID NO: 2452)5′-ACGAUAUCAUCACCAAGUUCCUGGAAA-3′ (SEQ ID NO: 2873)3′-UGCUAUAGUAGUGGUUCAAGGACCUUU-5′ (SEQ ID NO: 2313)AAT-1165 Target: 5′-ACGATATCATCACCAAGTTCCTGGAAA-3′ (SEQ ID NO: 2453)5′-ACCAAGUUCCUGGAAAAUGAAGACAGA-3′ (SEQ ID NO: 2874)3′-UGGUUCAAGGACCUUUUACUUCUGUCU-5′ (SEQ ID NO: 2314)AAT-1176 Target: 5′-ACCAAGTTCCTGGAAAATGAAGACAGA-3′ (SEQ ID NO: 2454)5′-GUCCAUUACUGGAACCUAUGAUCUGAA-3′ (SEQ ID NO: 2875)3′-CAGGUAAUGACCUUGGAUACUAGACUU-5′ (SEQ ID NO: 2315)AAT-1232 Target: 5′-GTCCATTACTGGAACCTATGATCTGAA-3′ (SEQ ID NO: 2455)5′-UCCAUUACUGGAACCUAUGAUCUGAAG-3′ (SEQ ID NO: 2876)3′-AGGUAAUGACCUUGGAUACUAGACUUC-5′ (SEQ ID NO: 2316)AAT-1233 Target: 5′-TCCATTACTGGAACCTATGATCTGAAG-3′ (SEQ ID NO: 2456)5′-CCAUUACUGGAACCUAUGAUCUGAAGA-3′ (SEQ ID NO: 2877)3′-GGUAAUGACCUUGGAUACUAGACUUCU-5′ (SEQ ID NO: 2317)AAT-1234 Target: 5′-CCATTACTGGAACCTATGATCTGAAGA-3′ (SEQ ID NO: 2457)5′-CAUUACUGGAACCUAUGAUCUGAAGAG-3′ (SEQ ID NO: 2878)3′-GUAAUGACCUUGGAUACUAGACUUCUC-5′ (SEQ ID NO: 2318)AAT-1235 Target: 5′-CATTACTGGAACCTATGATCTGAAGAG-3′ (SEQ ID NO: 2458)5′-AUUACUGGAACCUAUGAUCUGAAGAGC-3′ (SEQ ID NO: 2879)3′-UAAUGACCUUGGAUACUAGACUUCUCG-5′ (SEQ ID NO: 2319)AAT-1236 Target: 5′-ATTACTGGAACCTATGATCTGAAGAGC-3′ (SEQ ID NO: 2459)5′-UUACUGGAACCUAUGAUCUGAAGAGCG-3′ (SEQ ID NO: 2880)3′-AAUGACCUUGGAUACUAGACUUCUCGC-5′ (SEQ ID NO: 2320)AAT-1237 Target: 5′-TTACTGGAACCTATGATCTGAAGAGCG-3′ (SEQ ID NO: 2460)5′-UACUGGAACCUAUGAUCUGAAGAGCGU-3′ (SEQ ID NO: 2881)3′-AUGACCUUGGAUACUAGACUUCUCGCA-5′ (SEQ ID NO: 2321)AAT-1238 Target: 5′-TACTGGAACCTATGATCTGAAGAGCGT-3′ (SEQ ID NO: 2461)5′-ACUGGAACCUAUGAUCUGAAGAGCGUC-3′ (SEQ ID NO: 2882)3′-UGACCUUGGAUACUAGACUUCUCGCAG-5′ (SEQ ID NO: 2322)AAT-1239 Target: 5′-ACTGGAACCTATGATCTGAAGAGCGTC-3′ (SEQ ID NO: 2462)5′-CUGGAACCUAUGAUCUGAAGAGCGUCC-3′ (SEQ ID NO: 2883)3′-GACCUUGGAUACUAGACUUCUCGCAGG-5′ (SEQ ID NO: 2323)AAT-1240 Target: 5′-CTGGAACCTATGATCTGAAGAGCGTCC-3′ (SEQ ID NO: 2463)5′-GCAUCACUAAGGUCUUCAGCAAUGGGG-3′ (SEQ ID NO: 2884)3′-CGUAGUGAUUCCAGAAGUCGUUACCCC-5′ (SEQ ID NO: 2324)AAT-1279 Target: 5′-GCATCACTAAGGTCTTCAGCAATGGGG-3′ (SEQ ID NO: 2464)5′-CAUCACUAAGGUCUUCAGCAAUGGGGC-3′ (SEQ ID NO: 2885)3′-GUAGUGAUUCCAGAAGUCGUUACCCCG-5′ (SEQ ID NO: 2325)AAT-1280 Target: 5′-CATCACTAAGGTCTTCAGCAATGGGGC-3′ (SEQ ID NO: 2465)5′-AUCACUAAGGUCUUCAGCAAUGGGGCU-3′ (SEQ ID NO: 2886)3′-UAGUGAUUCCAGAAGUCGUUACCCCGA-5′ (SEQ ID NO: 2326)AAT-1281 Target: 5′-ATCACTAAGGTCTTCAGCAATGGGGCT-3′ (SEQ ID NO: 2466)5′-CACUAAGGUCUUCAGCAAUGGGGCUGA-3′ (SEQ ID NO: 2887)3′-GUGAUUCCAGAAGUCGUUACCCCGACU-5′ (SEQ ID NO: 2327)AAT-1283 Target: 5′-CACTAAGGTCTTCAGCAATGGGGCTGA-3′ (SEQ ID NO: 2467)5′-ACUAAGGUCUUCAGCAAUGGGGCUGAC-3′ (SEQ ID NO: 2888)3′-UGAUUCCAGAAGUCGUUACCCCGACUG-5′ (SEQ ID NO: 2328)AAT-1284 Target: 5′-ACTAAGGTCTTCAGCAATGGGGCTGAC-3′ (SEQ ID NO: 2468)5′-CCUGAAGCUCUCCAAGGCCGUGCAUAA-3′ (SEQ ID NO: 2889)3′-GGACUUCGAGAGGUUCCGGCACGUAUU-5′ (SEQ ID NO: 2329)AAT-1337 Target: 5′-CCTGAAGCTCTCCAAGGCCGTGCATAA-3′ (SEQ ID NO: 2469)5′-CUGAAGCUCUCCAAGGCCGUGCAUAAG-3′ (SEQ ID NO: 2890)3′-GACUUCGAGAGGUUCCGGCACGUAUUC-5′ (SEQ ID NO: 2330)AAT-1338 Target: 5′-CTGAAGCTCTCCAAGGCCGTGCATAAG-3′ (SEQ ID NO: 2470)5′-UGAAGCUCUCCAAGGCCGUGCAUAAGG-3′ (SEQ ID NO: 2891)3′-ACUUCGAGAGGUUCCGGCACGUAUUCC-5′ (SEQ ID NO: 2331)AAT-1339 Target: 5′-TGAAGCTCTCCAAGGCCGTGCATAAGG-3′ (SEQ ID NO: 2471)5′-CCCCGAGGUCAAGUUCAACAAACCCUU-3′ (SEQ ID NO: 2892)3′-GGGGCUCCAGUUCAAGUUGUUUGGGAA-5′ (SEQ ID NO: 2332)AAT-1442 Target: 5′-CCCCGAGGTCAAGTTCAACAAACCCTT-3′ (SEQ ID NO: 2472)5′-CCCGAGGUCAAGUUCAACAAACCCUUU-3′ (SEQ ID NO: 2893)3′-GGGCUCCAGUUCAAGUUGUUUGGGAAA-5′ (SEQ ID NO: 2333)AAT-1443 Target: 5′-CCCGAGGTCAAGTTCAACAAACCCTTT-3′ (SEQ ID NO: 2473)5′-CCGAGGUCAAGUUCAACAAACCCUUUG-3′ (SEQ ID NO: 2894)3′-GGCUCCAGUUCAAGUUGUUUGGGAAAC-5′ (SEQ ID NO: 2334)AAT-1444 Target: 5′-CCGAGGTCAAGTTCAACAAACCCTTTG-3′ (SEQ ID NO: 2474)5′-CGAGGUCAAGUUCAACAAACCCUUUGU-3′ (SEQ ID NO: 2895)3′-GCUCCAGUUCAAGUUGUUUGGGAAACA-5′ (SEQ ID NO: 2335)AAT-1445 Target: 5′-CGAGGTCAAGTTCAACAAACCCTTTGT-3′ (SEQ ID NO: 2475)5′-GAGGUCAAGUUCAACAAACCCUUUGUC-3′ (SEQ ID NO: 2896)3′-CUCCAGUUCAAGUUGUUUGGGAAACAG-5′ (SEQ ID NO: 2336)AAT-1446 Target: 5′-GAGGTCAAGTTCAACAAACCCTTTGTC-3′ (SEQ ID NO: 2476)5′-AGGUCAAGUUCAACAAACCCUUUGUCU-3′ (SEQ ID NO: 2897)3′-UCCAGUUCAAGUUGUUUGGGAAACAGA-5′ (SEQ ID NO: 2337)AAT-1447 Target: 5′-AGGTCAAGTTCAACAAACCCTTTGTCT-3′ (SEQ ID NO: 2477)5′-GGUCAAGUUCAACAAACCCUUUGUCUU-3′ (SEQ ID NO: 2898)3′-CCAGUUCAAGUUGUUUGGGAAACAGAA-5′ (SEQ ID NO: 2338)AAT-1448 Target: 5′-GGTCAAGTTCAACAAACCCTTTGTCTT-3′ (SEQ ID NO: 2478)5′-GUCAAGUUCAACAAACCCUUUGUCUUC-3′ (SEQ ID NO: 2899)3′-CAGUUCAAGUUGUUUGGGAAACAGAAG-5′ (SEQ ID NO: 2339)AAT-1449 Target: 5′-GTCAAGTTCAACAAACCCTTTGTCTTC-3′ (SEQ ID NO: 2479)5′-UCAAGUUCAACAAACCCUUUGUCUUCU-3′ (SEQ ID NO: 2900)3′-AGUUCAAGUUGUUUGGGAAACAGAAGA-5′ (SEQ ID NO: 2340)AAT-1450 Target: 5′-TCAAGTTCAACAAACCCTTTGTCTTCT-3′ (SEQ ID NO: 2480)5′-CAAGUUCAACAAACCCUUUGUCUUCUU-3′ (SEQ ID NO: 2 901)3′-GUUCAAGUUGUUUGGGAAACAGAAGAA-5′ (SEQ ID NO: 2341)AAT-1451 Target: 5′-CAAGTTCAACAAACCCTTTGTCTTCTT-3′ (SEQ ID NO: 2481)

TABLE 16Further DsiRNA Component 19 Nucleotide Target Sequences in α-1 antitrypsinmRNAAAT-366 19 nt Target #1: 5′-CCAGGGAGAUGCUGCCCAG-3′ (SEQ ID NO: 2902)AAT-366 19 nt Target #2: 5′-CCCAGGGAGAUGCUGCCCA-3′ (SEQ ID NO: 3042)AAT-366 19 nt Target #3: 5′-CCCCAGGGAGAUGCUGCCC-3′ (SEQ ID NO: 3182)AAT-367 19 nt Target #1: 5′-CAGGGAGAUGCUGCCCAGA-3′ (SEQ ID NO: 2903)AAT-367 19 nt Target #2: 5′-CCAGGGAGAUGCUGCCCAG-3′ (SEQ ID NO: 3043)AAT-367 19 nt Target #3: 5′-CCCAGGGAGAUGCUGCCCA-3′ (SEQ ID NO: 3183)AAT-368 19 nt Target #1: 5′-AGGGAGAUGCUGCCCAGAA-3′ (SEQ ID NO: 2904)AAT-368 19 nt Target #2: 5′-CAGGGAGAUGCUGCCCAGA-3′ (SEQ ID NO: 3044)AAT-368 19 nt Target #3: 5′-CCAGGGAGAUGCUGCCCAG-3′ (SEQ ID NO: 3184)AAT-369 19 nt Target #1: 5′-GGGAGAUGCUGCCCAGAAG-3′ (SEQ ID NO: 2905)AAT-369 19 nt Target #2: 5′-AGGGAGAUGCUGCCCAGAA-3′ (SEQ ID NO: 3045)AAT-369 19 nt Target #3: 5′-CAGGGAGAUGCUGCCCAGA-3′ (SEQ ID NO: 3185)AAT-370 19 nt Target #1: 5′-GGAGAUGCUGCCCAGAAGA-3′ (SEQ ID NO: 2906)AAT-370 19 nt Target #2: 5′-GGGAGAUGCUGCCCAGAAG-3′ (SEQ ID NO: 3046)AAT-370 19 nt Target #3: 5′-AGGGAGAUGCUGCCCAGAA-3′ (SEQ ID NO: 3186)AAT-371 19 nt Target #1: 5′-GAGAUGCUGCCCAGAAGAC-3′ (SEQ ID NO: 2907)AAT-371 19 nt Target #2: 5′-GGAGAUGCUGCCCAGAAGA-3′ (SEQ ID NO: 3047)AAT-371 19 nt Target #3: 5′-GGGAGAUGCUGCCCAGAAG-3′ (SEQ ID NO: 3187)AAT-391 19 nt Target #1: 5′-GAUACAUCCCACCAUGAUC-3′ (SEQ ID NO: 2908)AAT-391 19 nt Target #2: 5′-AGAUACAUCCCACCAUGAU-3′ (SEQ ID NO: 3048)AAT-391 19 nt Target #3: 5′-CAGAUACAUCCCACCAUGA-3′ (SEQ ID NO: 3188)AAT-392 19 nt Target #1: 5′-AUACAUCCCACCAUGAUCA-3′ (SEQ ID NO: 2909)AAT-392 19 nt Target #2: 5′-GAUACAUCCCACCAUGAUC-3′ (SEQ ID NO: 3049)AAT-392 19 nt Target #3: 5′-AGAUACAUCCCACCAUGAU-3′ (SEQ ID NO: 3189)AAT-393 19 nt Target #1: 5′-UACAUCCCACCAUGAUCAG-3′ (SEQ ID NO: 2910)AAT-393 19 nt Target #2: 5′-AUACAUCCCACCAUGAUCA-3′ (SEQ ID NO: 3050)AAT-393 19 nt Target #3: 5′-GAUACAUCCCACCAUGAUC-3′ (SEQ ID NO: 3190)AAT-394 19 nt Target #1: 5′-ACAUCCCACCAUGAUCAGG-3′ (SEQ ID NO: 2911)AAT-394 19 nt Target #2: 5′-UACAUCCCACCAUGAUCAG-3′ (SEQ ID NO: 3051)AAT-394 19 nt Target #3: 5′-AUACAUCCCACCAUGAUCA-3′ (SEQ ID NO: 3191)AAT-485 19 nt Target #1: 5′-ACCAGUCCAACAGCACCAA-3′ (SEQ ID NO: 2912)AAT-485 19 nt Target #2: 5′-CACCAGUCCAACAGCACCA-3′ (SEQ ID NO: 3052)AAT-485 19 nt Target #3: 5′-ACACCAGUCCAACAGCACC-3′ (SEQ ID NO: 3192)AAT-486 19 nt Target #1: 5′-CCAGUCCAACAGCACCAAU-3′ (SEQ ID NO: 2913)AAT-486 19 nt Target #2: 5′-ACCAGUCCAACAGCACCAA-3′ (SEQ ID NO: 3053)AAT-486 19 nt Target #3: 5′-CACCAGUCCAACAGCACCA-3′ (SEQ ID NO: 3193)AAT-487 19 nt Target #1: 5′-CAGUCCAACAGCACCAAUA-3′ (SEQ ID NO: 2914)AAT-487 19 nt Target #2: 5′-CCAGUCCAACAGCACCAAU-3′ (SEQ ID NO: 3054)AAT-487 19 nt Target #3: 5′-ACCAGUCCAACAGCACCAA-3′ (SEQ ID NO: 3194)AAT-488 19 nt Target #1: 5′-AGUCCAACAGCACCAAUAU-3′ (SEQ ID NO: 2915)AAT-488 19 nt Target #2: 5′-CAGUCCAACAGCACCAAUA-3′ (SEQ ID NO: 3055)AAT-488 19 nt Target #3: 5′-CCAGUCCAACAGCACCAAU-3′ (SEQ ID NO: 3195)AAT-489 19 nt Target #1: 5′-GUCCAACAGCACCAAUAUC-3′ (SEQ ID NO: 2916)AAT-489 19 nt Target #2: 5′-AGUCCAACAGCACCAAUAU-3′ (SEQ ID NO: 3056)AAT-489 19 nt Target #3: 5′-CAGUCCAACAGCACCAAUA-3′ (SEQ ID NO: 3196)AAT-490 19 nt Target #1: 5′-UCCAACAGCACCAAUAUCU-3′ (SEQ ID NO: 2917)AAT-490 19 nt Target #2: 5′-GUCCAACAGCACCAAUAUC-3′ (SEQ ID NO: 3057)AAT-490 19 nt Target #3: 5′-AGUCCAACAGCACCAAUAU-3′ (SEQ ID NO: 3197)AAT-491 19 nt Target #1: 5′-CCAACAGCACCAAUAUCUU-3′ (SEQ ID NO: 2918)AAT-491 19 nt Target #2: 5′-UCCAACAGCACCAAUAUCU-3′ (SEQ ID NO: 3058)AAT-491 19 nt Target #3: 5′-GUCCAACAGCACCAAUAUC-3′ (SEQ ID NO: 3198)AAT-492 19 nt Target #1: 5′-CAACAGCACCAAUAUCUUC-3′ (SEQ ID NO: 2919)AAT-492 19 nt Target #2: 5′-CCAACAGCACCAAUAUCUU-3′ (SEQ ID NO: 3059)AAT-492 19 nt Target #3: 5′-UCCAACAGCACCAAUAUCU-3′ (SEQ ID NO: 3199)AAT-493 19 nt Target #1: 5′-AACAGCACCAAUAUCUUCU-3′ (SEQ ID NO: 2920)AAT-493 19 nt Target #2: 5′-CAACAGCACCAAUAUCUUC-3′ (SEQ ID NO: 3060)AAT-493 19 nt Target #3: 5′-CCAACAGCACCAAUAUCUU-3′ (SEQ ID NO: 3200)AAT-494 19 nt Target #1: 5′-ACAGCACCAAUAUCUUCUU-3′ (SEQ ID NO: 2921)AAT-494 19 nt Target #2: 5′-AACAGCACCAAUAUCUUCU-3′ (SEQ ID NO: 3061)AAT-494 19 nt Target #3: 5′-CAACAGCACCAAUAUCUUC-3′ (SEQ ID NO: 3201)AAT-495 19 nt Target #1: 5′-CAGCACCAAUAUCUUCUUC-3′ (SEQ ID NO: 2922)AAT-495 19 nt Target #2: 5′-ACAGCACCAAUAUCUUCUU-3′ (SEQ ID NO: 3062)AAT-495 19 nt Target #3: 5′-AACAGCACCAAUAUCUUCU-3′ (SEQ ID NO: 3202)AAT-496 19 nt Target #1: 5′-AGCACCAAUAUCUUCUUCU-3′ (SEQ ID NO: 2923)AAT-496 19 nt Target #2: 5′-CAGCACCAAUAUCUUCUUC-3′ (SEQ ID NO: 3063)AAT-496 19 nt Target #3: 5′-ACAGCACCAAUAUCUUCUU-3′ (SEQ ID NO: 3203)AAT-497 19 nt Target #1: 5′-GCACCAAUAUCUUCUUCUC-3′ (SEQ ID NO: 2924)AAT-497 19 nt Target #2: 5′-AGCACCAAUAUCUUCUUCU-3′ (SEQ ID NO: 3064)AAT-497 19 nt Target #3: 5′-CAGCACCAAUAUCUUCUUC-3′ (SEQ ID NO: 3204)AAT-498 19 nt Target #1: 5′-CACCAAUAUCUUCUUCUCC-3′ (SEQ ID NO: 2925)AAT-498 19 nt Target #2: 5′-GCACCAAUAUCUUCUUCUC-3′ (SEQ ID NO: 3065)AAT-498 19 nt Target #3: 5′-AGCACCAAUAUCUUCUUCU-3′ (SEQ ID NO: 3205)AAT-499 19 nt Target #1: 5′-ACCAAUAUCUUCUUCUCCC-3′ (SEQ ID NO: 2926)AAT-499 19 nt Target #2: 5′-CACCAAUAUCUUCUUCUCC-3′ (SEQ ID NO: 3066)AAT-499 19 nt Target #3: 5′-GCACCAAUAUCUUCUUCUC-3′ (SEQ ID NO: 3206)AAT-516 19 nt Target #1: 5′-CCCAGUGAGCAUCGCUACA-3′ (SEQ ID NO: 2927)AAT-516 19 nt Target #2: 5′-CCCCAGUGAGCAUCGCUAC-3′ (SEQ ID NO: 3067)AAT-516 19 nt Target #3: 5′-UCCCCAGUGAGCAUCGCUA-3′ (SEQ ID NO: 3207)AAT-517 19 nt Target #1: 5′-CCAGUGAGCAUCGCUACAG-3′ (SEQ ID NO: 2928)AAT-517 19 nt Target #2: 5′-CCCAGUGAGCAUCGCUACA-3′ (SEQ ID NO: 3068)AAT-517 19 nt Target #3: 5′-CCCCAGUGAGCAUCGCUAC-3′ (SEQ ID NO: 3208)AAT-518 19 nt Target #1: 5′-CAGUGAGCAUCGCUACAGC-3′ (SEQ ID NO: 2929)AAT-518 19 nt Target #2: 5′-CCAGUGAGCAUCGCUACAG-3′ (SEQ ID NO: 3069)AAT-518 19 nt Target #3: 5′-CCCAGUGAGCAUCGCUACA-3′ (SEQ ID NO: 3209)AAT-519 19 nt Target #1: 5′-AGUGAGCAUCGCUACAGCC-3′ (SEQ ID NO: 2930)AAT-519 19 nt Target #2: 5′-CAGUGAGCAUCGCUACAGC-3′ (SEQ ID NO: 3070)AAT-519 19 nt Target #3: 5′-CCAGUGAGCAUCGCUACAG-3′ (SEQ ID NO: 3210)AAT-520 19 nt Target #1: 5′-GUGAGCAUCGCUACAGCCU-3′ (SEQ ID NO: 2931)AAT-520 19 nt Target #2: 5′-AGUGAGCAUCGCUACAGCC-3′ (SEQ ID NO: 3071)AAT-520 19 nt Target #3: 5′-CAGUGAGCAUCGCUACAGC-3′ (SEQ ID NO: 3211)AAT-521 19 nt Target #1: 5′-UGAGCAUCGCUACAGCCUU-3′ (SEQ ID NO: 2932)AAT-521 19 nt Target #2: 5′-GUGAGCAUCGCUACAGCCU-3′ (SEQ ID NO: 3072)AAT-521 19 nt Target #3: 5′-AGUGAGCAUCGCUACAGCC-3′ (SEQ ID NO: 3212)AAT-522 19 nt Target #1: 5′-GAGCAUCGCUACAGCCUUU-3′ (SEQ ID NO: 2933)AAT-522 19 nt Target #2: 5′-UGAGCAUCGCUACAGCCUU-3′ (SEQ ID NO: 3073)AAT-522 19 nt Target #3: 5′-GUGAGCAUCGCUACAGCCU-3′ (SEQ ID NO: 3213)AAT-523 19 nt Target #1: 5′-AGCAUCGCUACAGCCUUUG-3′ (SEQ ID NO: 2934)AAT-523 19 nt Target #2: 5′-GAGCAUCGCUACAGCCUUU-3′ (SEQ ID NO: 3074)AAT-523 19 nt Target #3: 5′-UGAGCAUCGCUACAGCCUU-3′ (SEQ ID NO: 3214)AAT-524 19 nt Target #1: 5′-GCAUCGCUACAGCCUUUGC-3′ (SEQ ID NO: 2935)AAT-524 19 nt Target #2: 5′-AGCAUCGCUACAGCCUUUG-3′ (SEQ ID NO: 3075)AAT-524 19 nt Target #3: 5′-GAGCAUCGCUACAGCCUUU-3′ (SEQ ID NO: 3215)AAT-525 19 nt Target #1: 5′-CAUCGCUACAGCCUUUGCA-3′ (SEQ ID NO: 2936)AAT-525 19 nt Target #2: 5′-GCAUCGCUACAGCCUUUGC-3′ (SEQ ID NO: 3076)AAT-525 19 nt Target #3: 5′-AGCAUCGCUACAGCCUUUG-3′ (SEQ ID NO: 3216)AAT-526 19 nt Target #1: 5′-AUCGCUACAGCCUUUGCAA-3′ (SEQ ID NO: 2937)AAT-526 19 nt Target #2: 5′-CAUCGCUACAGCCUUUGCA-3′ (SEQ ID NO: 3077)AAT-526 19 nt Target #3: 5′-GCAUCGCUACAGCCUUUGC-3′ (SEQ ID NO: 3217)AAT-527 19 nt Target #1: 5′-UCGCUACAGCCUUUGCAAU-3′ (SEQ ID NO: 2938)AAT-527 19 nt Target #2: 5′-AUCGCUACAGCCUUUGCAA-3′ (SEQ ID NO: 3078)AAT-527 19 nt Target #3: 5′-CAUCGCUACAGCCUUUGCA-3′ (SEQ ID NO: 3218)AAT-528 19 nt Target #1: 5′-CGCUACAGCCUUUGCAAUG-3′ (SEQ ID NO: 2939)AAT-528 19 nt Target #2: 5′-UCGCUACAGCCUUUGCAAU-3′ (SEQ ID NO: 3079)AAT-528 19 nt Target #3: 5′-AUCGCUACAGCCUUUGCAA-3′ (SEQ ID NO: 3219)AAT-529 19 nt Target #1: 5′-GCUACAGCCUUUGCAAUGC-3′ (SEQ ID NO: 2940)AAT-529 19 nt Target #2: 5′-CGCUACAGCCUUUGCAAUG-3′ (SEQ ID NO: 3080)AAT-529 19 nt Target #3: 5′-UCGCUACAGCCUUUGCAAU-3′ (SEQ ID NO: 3220)AAT-530 19 nt Target #1: 5′-CUACAGCCUUUGCAAUGCU-3′ (SEQ ID NO: 2941)AAT-530 19 nt Target #2: 5′-GCUACAGCCUUUGCAAUGC-3′ (SEQ ID NO: 3081)AAT-530 19 nt Target #3: 5′-CGCUACAGCCUUUGCAAUG-3′ (SEQ ID NO: 3221)AAT-531 19 nt Target #1: 5′-UACAGCCUUUGCAAUGCUC-3′ (SEQ ID NO: 2942)AAT-531 19 nt Target #2: 5′-CUACAGCCUUUGCAAUGCU-3′ (SEQ ID NO: 3082)AAT-531 19 nt Target #3: 5′-GCUACAGCCUUUGCAAUGC-3′ (SEQ ID NO: 3222)AAT-552 19 nt Target #1: 5′-CCUGGGGACCAAGGCUGAC-3′ (SEQ ID NO: 2943)AAT-552 19 nt Target #2: 5′-CCCUGGGGACCAAGGCUGA-3′ (SEQ ID NO: 3083)AAT-552 19 nt Target #3: 5′-UCCCUGGGGACCAAGGCUG-3′ (SEQ ID NO: 3223)AAT-556 19 nt Target #1: 5′-GGGACCAAGGCUGACACUC-3′ (SEQ ID NO: 2944)AAT-556 19 nt Target #2: 5′-GGGGACCAAGGCUGACACU-3′ (SEQ ID NO: 3084)AAT-556 19 nt Target #3: 5′-UGGGGACCAAGGCUGACAC-3′ (SEQ ID NO: 3224)AAT-557 19 nt Target #1: 5′-GGACCAAGGCUGACACUCA-3′ (SEQ ID NO: 2945)AAT-557 19 nt Target #2: 5′-GGGACCAAGGCUGACACUC-3′ (SEQ ID NO: 3085)AAT-557 19 nt Target #3: 5′-GGGGACCAAGGCUGACACU-3′ (SEQ ID NO: 3225)AAT-558 19 nt Target #1: 5′-GACCAAGGCUGACACUCAC-3′ (SEQ ID NO: 2946)AAT-558 19 nt Target #2: 5′-GGACCAAGGCUGACACUCA-3′ (SEQ ID NO: 3086)AAT-558 19 nt Target #3: 5′-GGGACCAAGGCUGACACUC-3′ (SEQ ID NO: 3226)AAT-579 19 nt Target #1: 5′-UGAAAUCCUGGAGGGCCUG-3′ (SEQ ID NO: 2947)AAT-579 19 nt Target #2: 5′-AUGAAAUCCUGGAGGGCCU-3′ (SEQ ID NO: 3087)AAT-579 19 nt Target #3: 5′-GAUGAAAUCCUGGAGGGCC-3′ (SEQ ID NO: 3227)AAT-580 19 nt Target #1: 5′-GAAAUCCUGGAGGGCCUGA-3′ (SEQ ID NO: 2948)AAT-580 19 nt Target #2: 5′-UGAAAUCCUGGAGGGCCUG-3′ (SEQ ID NO: 3088)AAT-580 19 nt Target #3: 5′-AUGAAAUCCUGGAGGGCCU-3′ (SEQ ID NO: 3228)AAT-632 19 nt Target #1: 5′-UCCAUGAAGGCUUCCAGGA-3′ (SEQ ID NO: 2949)AAT-632 19 nt Target #2: 5′-AUCCAUGAAGGCUUCCAGG-3′ (SEQ ID NO: 3089)AAT-632 19 nt Target #3: 5′-GAUCCAUGAAGGCUUCCAG-3′ (SEQ ID NO: 3229)AAT-633 19 nt Target #1: 5′-CCAUGAAGGCUUCCAGGAA-3′ (SEQ ID NO: 2950)AAT-633 19 nt Target #2: 5′-UCCAUGAAGGCUUCCAGGA-3′ (SEQ ID NO: 3090)AAT-633 19 nt Target #3: 5′-AUCCAUGAAGGCUUCCAGG-3′ (SEQ ID NO: 3230)AAT-801 19 nt Target #1: 5′-GGACACCGAAGAGGCCAAG-3′ (SEQ ID NO: 2951)AAT-801 19 nt Target #2: 5′-GGGACACCGAAGAGGCCAA-3′ (SEQ ID NO: 3091)AAT-801 19 nt Target #3: 5′-GGGGACACCGAAGAGGCCA-3′ (SEQ ID NO: 3231)AAT-802 19 nt Target #1: 5′-GACACCGAAGAGGCCAAGA-3′ (SEQ ID NO: 2952)AAT-802 19 nt Target #2: 5′-GGACACCGAAGAGGCCAAG-3′ (SEQ ID NO: 3092)AAT-802 19 nt Target #3: 5′-GGGACACCGAAGAGGCCAA-3′ (SEQ ID NO: 3232)AAT-803 19 nt Target #1: 5′-ACACCGAAGAGGCCAAGAA-3′ (SEQ ID NO: 2953)AAT-803 19 nt Target #2: 5′-GACACCGAAGAGGCCAAGA-3′ (SEQ ID NO: 3093)AAT-803 19 nt Target #3: 5′-GGACACCGAAGAGGCCAAG-3′ (SEQ ID NO: 3233)AAT-804 19 nt Target #1: 5′-CACCGAAGAGGCCAAGAAA-3′ (SEQ ID NO: 2954)AAT-804 19 nt Target #2: 5′-ACACCGAAGAGGCCAAGAA-3′ (SEQ ID NO: 3094)AAT-804 19 nt Target #3: 5′-GACACCGAAGAGGCCAAGA-3′ (SEQ ID NO: 3234)AAT-805 19 nt Target #1: 5′-ACCGAAGAGGCCAAGAAAC-3′ (SEQ ID NO: 2955)AAT-805 19 nt Target #2: 5′-CACCGAAGAGGCCAAGAAA-3′ (SEQ ID NO: 3095)AAT-805 19 nt Target #3: 5′-ACACCGAAGAGGCCAAGAA-3′ (SEQ ID NO: 3235)AAT-806 19 nt Target #1: 5′-CCGAAGAGGCCAAGAAACA-3′ (SEQ ID NO: 2956)AAT-806 19 nt Target #2: 5′-ACCGAAGAGGCCAAGAAAC-3′ (SEQ ID NO: 3096)AAT-806 19 nt Target #3: 5′-CACCGAAGAGGCCAAGAAA-3′ (SEQ ID NO: 3236)AAT-807 19 nt Target #1: 5′-CGAAGAGGCCAAGAAACAG-3′ (SEQ ID NO: 2957)AAT-807 19 nt Target #2: 5′-CCGAAGAGGCCAAGAAACA-3′ (SEQ ID NO: 3097)AAT-807 19 nt Target #3: 5′-ACCGAAGAGGCCAAGAAAC-3′ (SEQ ID NO: 3237)AAT-808 19 nt Target #1: 5′-GAAGAGGCCAAGAAACAGA-3′ (SEQ ID NO: 2958)AAT-808 19 nt Target #2: 5′-CGAAGAGGCCAAGAAACAG-3′ (SEQ ID NO: 3098)AAT-808 19 nt Target #3: 5′-CCGAAGAGGCCAAGAAACA-3′ (SEQ ID NO: 3238)AAT-809 19 nt Target #1: 5′-AAGAGGCCAAGAAACAGAU-3′ (SEQ ID NO: 2959)AAT-809 19 nt Target #2: 5′-GAAGAGGCCAAGAAACAGA-3′ (SEQ ID NO: 3099)AAT-809 19 nt Target #3: 5′-CGAAGAGGCCAAGAAACAG-3′ (SEQ ID NO: 3239)AAT-810 19 nt Target #1: 5′-AGAGGCCAAGAAACAGAUC-3′ (SEQ ID NO: 2960)AAT-810 19 nt Target #2: 5′-AAGAGGCCAAGAAACAGAU-3′ (SEQ ID NO: 3100)AAT-810 19 nt Target #3: 5′-GAAGAGGCCAAGAAACAGA-3′ (SEQ ID NO: 3240)AAT-811 19 nt Target #1: 5′-GAGGCCAAGAAACAGAUCA-3′ (SEQ ID NO: 2961)AAT-811 19 nt Target #2: 5′-AGAGGCCAAGAAACAGAUC-3′ (SEQ ID NO: 3101)AAT-811 19 nt Target #3: 5′-AAGAGGCCAAGAAACAGAU-3′ (SEQ ID NO: 3241)AAT-812 19 nt Target #1: 5′-AGGCCAAGAAACAGAUCAA-3′ (SEQ ID NO: 2962)AAT-812 19 nt Target #2: 5′-GAGGCCAAGAAACAGAUCA-3′ (SEQ ID NO: 3102)AAT-812 19 nt Target #3: 5′-AGAGGCCAAGAAACAGAUC-3′ (SEQ ID NO: 3242)AAT-813 19 nt Target #1: 5′-GGCCAAGAAACAGAUCAAC-3′ (SEQ ID NO: 2963)AAT-813 19 nt Target #2: 5′-AGGCCAAGAAACAGAUCAA-3′ (SEQ ID NO: 3103)AAT-813 19 nt Target #3: 5′-GAGGCCAAGAAACAGAUCA-3′ (SEQ ID NO: 3243)AAT-900 19 nt Target #1: 5′-UUUUGCUCUGGUGAAUUAC-3′ (SEQ ID NO: 2964)AAT-900 19 nt Target #2: 5′-UUUUUGCUCUGGUGAAUUA-3′ (SEQ ID NO: 3104)AAT-900 19 nt Target #3: 5′-GUUUUUGCUCUGGUGAAUU-3′ (SEQ ID NO: 3244)AAT-901 19 nt Target #1: 5′-UUUGCUCUGGUGAAUUACA-3′ (SEQ ID NO: 2965)AAT-901 19 nt Target #2: 5′-UUUUGCUCUGGUGAAUUAC-3′ (SEQ ID NO: 3105)AAT-901 19 nt Target #3: 5′-UUUUUGCUCUGGUGAAUUA-3′ (SEQ ID NO: 3245)AAT-902 19 nt Target #1: 5′-UUGCUCUGGUGAAUUACAU-3′ (SEQ ID NO: 2966)AAT-902 19 nt Target #2: 5′-UUUGCUCUGGUGAAUUACA-3′ (SEQ ID NO: 3106)AAT-902 19 nt Target #3: 5′-UUUUGCUCUGGUGAAUUAC-3′ (SEQ ID NO: 3246)AAT-903 19 nt Target #1: 5′-UGCUCUGGUGAAUUACAUC-3′ (SEQ ID NO: 2967)AAT-903 19 nt Target #2: 5′-UUGCUCUGGUGAAUUACAU-3′ (SEQ ID NO: 3107)AAT-903 19 nt Target #3: 5′-UUUGCUCUGGUGAAUUACA-3′ (SEQ ID NO: 3247)AAT-904 19 nt Target #1: 5′-GCUCUGGUGAAUUACAUCU-3′ (SEQ ID NO: 2968)AAT-904 19 nt Target #2: 5′-UGCUCUGGUGAAUUACAUC-3′ (SEQ ID NO: 3108)AAT-904 19 nt Target #3: 5′-UUGCUCUGGUGAAUUACAU-3′ (SEQ ID NO: 3248)AAT-905 19 nt Target #1: 5′-CUCUGGUGAAUUACAUCUU-3′ (SEQ ID NO: 2969)AAT-905 19 nt Target #2: 5′-GCUCUGGUGAAUUACAUCU-3′ (SEQ ID NO: 3109)AAT-905 19 nt Target #3: 5′-UGCUCUGGUGAAUUACAUC-3′ (SEQ ID NO: 3249)AAT-906 19 nt Target #1: 5′-UCUGGUGAAUUACAUCUUC-3′ (SEQ ID NO: 2970)AAT-906 19 nt Target #2: 5′-CUCUGGUGAAUUACAUCUU-3′ (SEQ ID NO: 3110)AAT-906 19 nt Target #3: 5′-GCUCUGGUGAAUUACAUCU-3′ (SEQ ID NO: 3250)AAT-907 19 nt Target #1: 5′-CUGGUGAAUUACAUCUUCU-3′ (SEQ ID NO: 2971)AAT-907 19 nt Target #2: 5′-UCUGGUGAAUUACAUCUUC-3′ (SEQ ID NO: 3111)AAT-907 19 nt Target #3: 5′-CUCUGGUGAAUUACAUCUU-3′ (SEQ ID NO: 3251)AAT-908 19 nt Target #1: 5′-UGGUGAAUUACAUCUUCUU-3′ (SEQ ID NO: 2972)AAT-908 19 nt Target #2: 5′-CUGGUGAAUUACAUCUUCU-3′ (SEQ ID NO: 3112)AAT-908 19 nt Target #3: 5′-UCUGGUGAAUUACAUCUUC-3′ (SEQ ID NO: 3252)AAT-909 19 nt Target #1: 5′-GGUGAAUUACAUCUUCUUU-3′ (SEQ ID NO: 2973)AAT-909 19 nt Target #2: 5′-UGGUGAAUUACAUCUUCUU-3′ (SEQ ID NO: 3113)AAT-909 19 nt Target #3: 5′-CUGGUGAAUUACAUCUUCU-3′ (SEQ ID NO: 3253)AAT-910 19 nt Target #1: 5′-GUGAAUUACAUCUUCUUUA-3′ (SEQ ID NO: 2974)AAT-910 19 nt Target #2: 5′-GGUGAAUUACAUCUUCUUU-3′ (SEQ ID NO: 3114)AAT-910 19 nt Target #3: 5′-UGGUGAAUUACAUCUUCUU-3′ (SEQ ID NO: 3254)AAT-911 19 nt Target #1: 5′-UGAAUUACAUCUUCUUUAA-3′ (SEQ ID NO: 2975)AAT-911 19 nt Target #2: 5′-GUGAAUUACAUCUUCUUUA-3′ (SEQ ID NO: 3115)AAT-911 19 nt Target #3: 5′-GGUGAAUUACAUCUUCUUU-3′ (SEQ ID NO: 3255)AAT-912 19 nt Target #1: 5′-GAAUUACAUCUUCUUUAAA-3′ (SEQ ID NO: 2976)AAT-912 19 nt Target #2: 5′-UGAAUUACAUCUUCUUUAA-3′ (SEQ ID NO: 3116)AAT-912 19 nt Target #3: 5′-GUGAAUUACAUCUUCUUUA-3′ (SEQ ID NO: 3256)AAT-913 19 nt Target #1: 5′-AAUUACAUCUUCUUUAAAG-3′ (SEQ ID NO: 2977)AAT-913 19 nt Target #2: 5′-GAAUUACAUCUUCUUUAAA-3′ (SEQ ID NO: 3117)AAT-913 19 nt Target #3: 5′-UGAAUUACAUCUUCUUUAA-3′ (SEQ ID NO: 3257)AAT-914 19 nt Target #1: 5′-AUUACAUCUUCUUUAAAGG-3′ (SEQ ID NO: 2978)AAT-914 19 nt Target #2: 5′-AAUUACAUCUUCUUUAAAG-3′ (SEQ ID NO: 3118)AAT-914 19 nt Target #3: 5′-GAAUUACAUCUUCUUUAAA-3′ (SEQ ID NO: 3258)AAT-915 19 nt Target #1: 5′-UUACAUCUUCUUUAAAGGC-3′ (SEQ ID NO: 2979)AAT-915 19 nt Target #2: 5′-AUUACAUCUUCUUUAAAGG-3′ (SEQ ID NO: 3119)AAT-915 19 nt Target #3: 5′-AAUUACAUCUUCUUUAAAG-3′ (SEQ ID NO: 3259)AAT-916 19 nt Target #1: 5′-UACAUCUUCUUUAAAGGCA-3′ (SEQ ID NO: 2980)AAT-916 19 nt Target #2: 5′-UUACAUCUUCUUUAAAGGC-3′ (SEQ ID NO: 3120)AAT-916 19 nt Target #3: 5′-AUUACAUCUUCUUUAAAGG-3′ (SEQ ID NO: 3260)AAT-917 19 nt Target #1: 5′-ACAUCUUCUUUAAAGGCAA-3′ (SEQ ID NO: 2981)AAT-917 19 nt Target #2: 5′-UACAUCUUCUUUAAAGGCA-3′ (SEQ ID NO: 3121)AAT-917 19 nt Target #3: 5′-UUACAUCUUCUUUAAAGGC-3′ (SEQ ID NO: 3261)AAT-918 19 nt Target #1: 5′-CAUCUUCUUUAAAGGCAAA-3′ (SEQ ID NO: 2982)AAT-918 19 nt Target #2: 5′-ACAUCUUCUUUAAAGGCAA-3′ (SEQ ID NO: 3122)AAT-918 19 nt Target #3: 5′-UACAUCUUCUUUAAAGGCA-3′ (SEQ ID NO: 3262)AAT-922 19 nt Target #1: 5′-UUCUUUAAAGGCAAAUGGG-3′ (SEQ ID NO: 2983)AAT-922 19 nt Target #2: 5′-CUUCUUUAAAGGCAAAUGG-3′ (SEQ ID NO: 3123)AAT-922 19 nt Target #3: 5′-UCUUCUUUAAAGGCAAAUG-3′ (SEQ ID NO: 3263)AAT-924 19 nt Target #1: 5′-CUUUAAAGGCAAAUGGGAG-3′ (SEQ ID NO: 2984)AAT-924 19 nt Target #2: 5′-UCUUUAAAGGCAAAUGGGA-3′ (SEQ ID NO: 3124)AAT-924 19 nt Target #3: 5′-UUCUUUAAAGGCAAAUGGG-3′ (SEQ ID NO: 3264)AAT-932 19 nt Target #1: 5′-GCAAAUGGGAGAGACCCUU-3′ (SEQ ID NO: 2985)AAT-932 19 nt Target #2: 5′-GGCAAAUGGGAGAGACCCU-3′ (SEQ ID NO: 3125)AAT-932 19 nt Target #3: 5′-AGGCAAAUGGGAGAGACCC-3′ (SEQ ID NO: 3265)AAT-933 19 nt Target #1: 5′-CAAAUGGGAGAGACCCUUU-3′ (SEQ ID NO: 2986)AAT-933 19 nt Target #2: 5′-GCAAAUGGGAGAGACCCUU-3′ (SEQ ID NO: 3126)AAT-933 19 nt Target #3: 5′-GGCAAAUGGGAGAGACCCU-3′ (SEQ ID NO: 3266)AAT-934 19 nt Target #1: 5′-AAAUGGGAGAGACCCUUUG-3′ (SEQ ID NO: 2987)AAT-934 19 nt Target #2: 5′-CAAAUGGGAGAGACCCUUU-3′ (SEQ ID NO: 3127)AAT-934 19 nt Target #3: 5′-GCAAAUGGGAGAGACCCUU-3′ (SEQ ID NO: 3267)AAT-935 19 nt Target #1: 5′-AAUGGGAGAGACCCUUUGA-3′ (SEQ ID NO: 2988)AAT-935 19 nt Target #2: 5′-AAAUGGGAGAGACCCUUUG-3′ (SEQ ID NO: 3128)AAT-935 19 nt Target #3: 5′-CAAAUGGGAGAGACCCUUU-3′ (SEQ ID NO: 3268)AAT-1061 19 nt Target #1: 5′-UGUCCAGCUGGGUGCUGCU-3 (SEQ ID NO: 2989)AAT-1061 19 nt Target #2: 5′-CUGUCCAGCUGGGUGCUGC-3 (SEQ ID NO: 3129)AAT-1061 19 nt Target #3: 5′-GCUGUCCAGCUGGGUGCUG-3 (SEQ ID NO: 3269)AAT-1062 19 nt Target #1: 5′-GUCCAGCUGGGUGCUGCUG-3 (SEQ ID NO: 2990)AAT-1062 19 nt Target #2: 5′-UGUCCAGCUGGGUGCUGCU-3 (SEQ ID NO: 3130)AAT-1062 19 nt Target #3: 5′-CUGUCCAGCUGGGUGCUGC-3 (SEQ ID NO: 3270)AAT-1063 19 nt Target #1: 5′-UCCAGCUGGGUGCUGCUGA-3 (SEQ ID NO: 2991)AAT-1063 19 nt Target #2: 5′-GUCCAGCUGGGUGCUGCUG-3 (SEQ ID NO: 3131)AAT-1063 19 nt Target #3: 5′-UGUCCAGCUGGGUGCUGCU-3 (SEQ ID NO: 3271)AAT-1064 19 nt Target #1: 5′-CCAGCUGGGUGCUGCUGAU-3 (SEQ ID NO: 2992)AAT-1064 19 nt Target #2: 5′-UCCAGCUGGGUGCUGCUGA-3 (SEQ ID NO: 3132)AAT-1064 19 nt Target #3: 5′-GUCCAGCUGGGUGCUGCUG-3 (SEQ ID NO: 3272)AAT-1065 19 nt Target #1: 5′-CAGCUGGGUGCUGCUGAUG-3 (SEQ ID NO: 2993)AAT-1065 19 nt Target #2: 5′-CCAGCUGGGUGCUGCUGAU-3 (SEQ ID NO: 3133)AAT-1065 19 nt Target #3: 5′-UCCAGCUGGGUGCUGCUGA-3 (SEQ ID NO: 3273)AAT-1066 19 nt Target #1: 5′-AGCUGGGUGCUGCUGAUGA-3 (SEQ ID NO: 2994)AAT-1066 19 nt Target #2: 5′-CAGCUGGGUGCUGCUGAUG-3 (SEQ ID NO: 3134)AAT-1066 19 nt Target #3: 5′-CCAGCUGGGUGCUGCUGAU-3 (SEQ ID NO: 3274)AAT-1067 19 nt Target #1: 5′-GCUGGGUGCUGCUGAUGAA-3 (SEQ ID NO: 2995)AAT-1067 19 nt Target #2: 5′-AGCUGGGUGCUGCUGAUGA-3 (SEQ ID NO: 3135)AAT-1067 19 nt Target #3: 5′-CAGCUGGGUGCUGCUGAUG-3 (SEQ ID NO: 3275)AAT-1068 19 nt Target #1: 5′-CUGGGUGCUGCUGAUGAAA-3 (SEQ ID NO: 2996)AAT-1068 19 nt Target #2: 5′-GCUGGGUGCUGCUGAUGAA-3 (SEQ ID NO: 3136)AAT-1068 19 nt Target #3: 5′-AGCUGGGUGCUGCUGAUGA-3′ (SEQ ID NO: 3276)AAT-1069 19 nt Target #1: 5′-UGGGUGCUGCUGAUGAAAU-3′ (SEQ ID NO: 2997)AAT-1069 19 nt Target #2: 5′-CUGGGUGCUGCUGAUGAAA-3′ (SEQ ID NO: 3137)AAT-1069 19 nt Target #3: 5′-GCUGGGUGCUGCUGAUGAA-3′ (SEQ ID NO: 3277)AAT-1070 19 nt Target #1: 5′-GGGUGCUGCUGAUGAAAUA-3′ (SEQ ID NO: 2998)AAT-1070 19 nt Target #2: 5′-UGGGUGCUGCUGAUGAAAU-3′ (SEQ ID NO: 3138)AAT-1070 19 nt Target #3: 5′-CUGGGUGCUGCUGAUGAAA-3′ (SEQ ID NO: 3278)AAT-1072 19 nt Target #1: 5′-GUGCUGCUGAUGAAAUACC-3′ (SEQ ID NO: 2999)AAT-1072 19 nt Target #2: 5′-GGUGCUGCUGAUGAAAUAC-3′ (SEQ ID NO: 3139)AAT-1072 19 nt Target #3: 5′-GGGUGCUGCUGAUGAAAUA-3′ (SEQ ID NO: 3279)AAT-1073 19 nt Target #1: 5′-UGCUGCUGAUGAAAUACCU-3′ (SEQ ID NO: 3000)AAT-1073 19 nt Target #2: 5′-GUGCUGCUGAUGAAAUACC-3′ (SEQ ID NO: 3140)AAT-1073 19 nt Target #3: 5′-GGUGCUGCUGAUGAAAUAC-3′ (SEQ ID NO: 3280)AAT-1074 19 nt Target #1: 5′-GCUGCUGAUGAAAUACCUG-3′ (SEQ ID NO: 3001)AAT-1074 19 nt Target #2: 5′-UGCUGCUGAUGAAAUACCU-3′ (SEQ ID NO: 3141)AAT-1074 19 nt Target #3: 5′-GUGCUGCUGAUGAAAUACC-3′ (SEQ ID NO: 3281)AAT-1075 19 nt Target #1: 5′-CUGCUGAUGAAAUACCUGG-3′ (SEQ ID NO: 3002)AAT-1075 19 nt Target #2: 5′-GCUGCUGAUGAAAUACCUG-3′ (SEQ ID NO: 3142)AAT-1075 19 nt Target #3: 5′-UGCUGCUGAUGAAAUACCU-3′ (SEQ ID NO: 3282)AAT-1076 19 nt Target #1: 5′-UGCUGAUGAAAUACCUGGG-3′ (SEQ ID NO: 3003)AAT-1076 19 nt Target #2: 5′-CUGCUGAUGAAAUACCUGG-3′ (SEQ ID NO: 3143)AAT-1076 19 nt Target #3: 5′-GCUGCUGAUGAAAUACCUG-3′ (SEQ ID NO: 3283)AAT-1077 19 nt Target #1: 5′-GCUGAUGAAAUACCUGGGC-3′ (SEQ ID NO: 3004)AAT-1077 19 nt Target #2: 5′-UGCUGAUGAAAUACCUGGG-3′ (SEQ ID NO: 3144)AAT-1077 19 nt Target #3: 5′-CUGCUGAUGAAAUACCUGG-3′ (SEQ ID NO: 3284)AAT-1078 19 nt Target #1: 5′-CUGAUGAAAUACCUGGGCA-3′ (SEQ ID NO: 3005)AAT-1078 19 nt Target #2: 5′-GCUGAUGAAAUACCUGGGC-3′ (SEQ ID NO: 3145)AAT-1078 19 nt Target #3: 5′-UGCUGAUGAAAUACCUGGG-3′ (SEQ ID NO: 3285)AAT-1079 19 nt Target #1: 5′-UGAUGAAAUACCUGGGCAA-3′ (SEQ ID NO: 3006)AAT-1079 19 nt Target #2: 5′-CUGAUGAAAUACCUGGGCA-3′ (SEQ ID NO: 3146)AAT-1079 19 nt Target #3: 5′-GCUGAUGAAAUACCUGGGC-3′ (SEQ ID NO: 3286)AAT-1080 19 nt Target #1: 5′-GAUGAAAUACCUGGGCAAU-3′ (SEQ ID NO: 3007)AAT-1080 19 nt Target #2: 5′-UGAUGAAAUACCUGGGCAA-3′ (SEQ ID NO: 3147)AAT-1080 19 nt Target #3: 5′-CUGAUGAAAUACCUGGGCA-3′ (SEQ ID NO: 3287)AAT-1081 19 nt Target #1: 5′-AUGAAAUACCUGGGCAAUG-3′ (SEQ ID NO: 3008)AAT-1081 19 nt Target #2: 5′-GAUGAAAUACCUGGGCAAU-3′ (SEQ ID NO: 3148)AAT-1081 19 nt Target #3: 5′-UGAUGAAAUACCUGGGCAA-3′ (SEQ ID NO: 3288)AAT-1083 19 nt Target #1: 5′-GAAAUACCUGGGCAAUGCC-3′ (SEQ ID NO: 3009)AAT-1083 19 nt Target #2: 5′-UGAAAUACCUGGGCAAUGC-3′ (SEQ ID NO: 3149)AAT-1083 19 nt Target #3: 5′-AUGAAAUACCUGGGCAAUG-3′ (SEQ ID NO: 3289)AAT-1138 19 nt Target #1: 5′-CAGCACCUGGAAAAUGAAC-3′ (SEQ ID NO: 3010)AAT-1138 19 nt Target #2: 5′-ACAGCACCUGGAAAAUGAA-3′ (SEQ ID NO: 3150)AAT-1138 19 nt Target #3: 5′-UACAGCACCUGGAAAAUGA-3′ (SEQ ID NO: 3290)AAT-1144 19 nt Target #1: 5′-CUGGAAAAUGAACUCACCC-3′ (SEQ ID NO: 3011)AAT-1144 19 nt Target #2: 5′-CCUGGAAAAUGAACUCACC-3′ (SEQ ID NO: 3151)AAT-1144 19 nt Target #3: 5′-ACCUGGAAAAUGAACUCAC-3′ (SEQ ID NO: 3291)AAT-1145 19 nt Target #1: 5′-UGGAAAAUGAACUCACCCA-3′ (SEQ ID NO: 3012)AAT-1145 19 nt Target #2: 5′-CUGGAAAAUGAACUCACCC-3′ (SEQ ID NO: 3152)AAT-1145 19 nt Target #3: 5′-CCUGGAAAAUGAACUCACC-3′ (SEQ ID NO: 3292)AAT-1165 19 nt Target #1: 5′-GAUAUCAUCACCAAGUUCC-3′ (SEQ ID NO: 3013)AAT-1165 19 nt Target #2: 5′-CGAUAUCAUCACCAAGUUC-3′ (SEQ ID NO: 3153)AAT-1165 19 nt Target #3: 5′-ACGAUAUCAUCACCAAGUU-3′ (SEQ ID NO: 3293)AAT-1176 19 nt Target #1: 5′-CAAGUUCCUGGAAAAUGAA-3′ (SEQ ID NO: 3014)AAT-1176 19 nt Target #2: 5′-CCAAGUUCCUGGAAAAUGA-3′ (SEQ ID NO: 3154)AAT-1176 19 nt Target #3: 5′-ACCAAGUUCCUGGAAAAUG-3′ (SEQ ID NO: 3294)AAT-1232 19 nt Target #1: 5′-CCAUUACUGGAACCUAUGA-3′ (SEQ ID NO: 3015)AAT-1232 19 nt Target #2: 5′-UCCAUUACUGGAACCUAUG-3′ (SEQ ID NO: 3155)AAT-1232 19 nt Target #3: 5′-GUCCAUUACUGGAACCUAU-3′ (SEQ ID NO: 3295)AAT-1233 19 nt Target #1: 5′-CAUUACUGGAACCUAUGAU-3′ (SEQ ID NO: 3016)AAT-1233 19 nt Target #2: 5′-CCAUUACUGGAACCUAUGA-3′ (SEQ ID NO: 3156)AAT-1233 19 nt Target #3: 5′-UCCAUUACUGGAACCUAUG-3′ (SEQ ID NO: 3296)AAT-1234 19 nt Target #1: 5′-AUUACUGGAACCUAUGAUC-3′ (SEQ ID NO: 3017)AAT-1234 19 nt Target #2: 5′-CAUUACUGGAACCUAUGAU-3′ (SEQ ID NO: 3157)AAT-1234 19 nt Target #3: 5′-CCAUUACUGGAACCUAUGA-3′ (SEQ ID NO: 3297)AAT-1235 19 nt Target #1: 5′-UUACUGGAACCUAUGAUCU-3′ (SEQ ID NO: 3018)AAT-1235 19 nt Target #2: 5′-AUUACUGGAACCUAUGAUC-3′ (SEQ ID NO: 3158)AAT-1235 19 nt Target #3: 5′-CAUUACUGGAACCUAUGAU-3′ (SEQ ID NO: 3298)AAT-1236 19 nt Target #1: 5′-UACUGGAACCUAUGAUCUG-3′ (SEQ ID NO: 3019)AAT-1236 19 nt Target #2: 5′-UUACUGGAACCUAUGAUCU-3′ (SEQ ID NO: 3159)AAT-1236 19 nt Target #3: 5′-AUUACUGGAACCUAUGAUC-3′ (SEQ ID NO: 3299)AAT-1237 19 nt Target #1: 5′-ACUGGAACCUAUGAUCUGA-3′ (SEQ ID NO: 3020)AAT-1237 19 nt Target #2: 5′-UACUGGAACCUAUGAUCUG-3′ (SEQ ID NO: 3160)AAT-1237 19 nt Target #3: 5′-UUACUGGAACCUAUGAUCU-3′ (SEQ ID NO: 3300)AAT-1238 19 nt Target #1: 5′-CUGGAACCUAUGAUCUGAA-3′ (SEQ ID NO: 3021)AAT-1238 19 nt Target #2: 5′-ACUGGAACCUAUGAUCUGA-3′ (SEQ ID NO: 3161)AAT-1238 19 nt Target #3: 5′-UACUGGAACCUAUGAUCUG-3′ (SEQ ID NO: 3301)AAT-1239 19 nt Target #1: 5′-UGGAACCUAUGAUCUGAAG-3′ (SEQ ID NO: 3022)AAT-1239 19 nt Target #2: 5′-CUGGAACCUAUGAUCUGAA-3′ (SEQ ID NO: 3162)AAT-1239 19 nt Target #3: 5′-ACUGGAACCUAUGAUCUGA-3′ (SEQ ID NO: 3302)AAT-1240 19 nt Target #1: 5′-GGAACCUAUGAUCUGAAGA-3′ (SEQ ID NO: 3023)AAT-1240 19 nt Target #2: 5′-UGGAACCUAUGAUCUGAAG-3′ (SEQ ID NO: 3163)AAT-1240 19 nt Target #3: 5′-CUGGAACCUAUGAUCUGAA-3′ (SEQ ID NO: 3303)AAT-1279 19 nt Target #1: 5′-AUCACUAAGGUCUUCAGCA-3′ (SEQ ID NO: 3024)AAT-1279 19 nt Target #2: 5′-CAUCACUAAGGUCUUCAGC-3′ (SEQ ID NO: 3164)AAT-1279 19 nt Target #3: 5′-GCAUCACUAAGGUCUUCAG-3′ (SEQ ID NO: 3304)AAT-1280 19 nt Target #1: 5′-UCACUAAGGUCUUCAGCAA-3′ (SEQ ID NO: 3025)AAT-1280 19 nt Target #2: 5′-AUCACUAAGGUCUUCAGCA-3′ (SEQ ID NO: 3165)AAT-1280 19 nt Target #3: 5′-CAUCACUAAGGUCUUCAGC-3′ (SEQ ID NO: 3305)AAT-1281 19 nt Target #1: 5′-CACUAAGGUCUUCAGCAAU-3′ (SEQ ID NO: 3026)AAT-1281 19 nt Target #2: 5′-UCACUAAGGUCUUCAGCAA-3′ (SEQ ID NO: 3166)AAT-1281 19 nt Target #3: 5′-AUCACUAAGGUCUUCAGCA-3′ (SEQ ID NO: 3306)AAT-1283 19 nt Target #1: 5′-CUAAGGUCUUCAGCAAUGG-3′ (SEQ ID NO: 3027)AAT-1283 19 nt Target #2: 5′-ACUAAGGUCUUCAGCAAUG-3′ (SEQ ID NO: 3167)AAT-1283 19 nt Target #3: 5′-CACUAAGGUCUUCAGCAAU-3′ (SEQ ID NO: 3307)AAT-1284 19 nt Target #1: 5′-UAAGGUCUUCAGCAAUGGG-3′ (SEQ ID NO: 3028)AAT-1284 19 nt Target #2: 5′-CUAAGGUCUUCAGCAAUGG-3′ (SEQ ID NO: 3168)AAT-1284 19 nt Target #3: 5′-ACUAAGGUCUUCAGCAAUG-3′ (SEQ ID NO: 3308)AAT-1337 19 nt Target #1: 5′-UGAAGCUCUCCAAGGCCGU-3′ (SEQ ID NO: 3029)AAT-1337 19 nt Target #2: 5′-CUGAAGCUCUCCAAGGCCG-3′ (SEQ ID NO: 3169)AAT-1337 19 nt Target #3: 5′-CCUGAAGCUCUCCAAGGCC-3′ (SEQ ID NO: 3309)AAT-1338 19 nt Target #1: 5′-GAAGCUCUCCAAGGCCGUG-3′ (SEQ ID NO: 3030)AAT-1338 19 nt Target #2: 5′-UGAAGCUCUCCAAGGCCGU-3′ (SEQ ID NO: 3170)AAT-1338 19 nt Target #3: 5′-CUGAAGCUCUCCAAGGCCG-3′ (SEQ ID NO: 3310)AAT-1339 19 nt Target #1: 5′-AAGCUCUCCAAGGCCGUGC-3′ (SEQ ID NO: 3031)AAT-1339 19 nt Target #2: 5′-GAAGCUCUCCAAGGCCGUG-3′ (SEQ ID NO: 3171)AAT-1339 19 nt Target #3: 5′-UGAAGCUCUCCAAGGCCGU-3′ (SEQ ID NO: 3311)AAT-1442 19 nt Target #1: 5′-CCGAGGUCAAGUUCAACAA-3′ (SEQ ID NO: 3032)AAT-1442 19 nt Target #2: 5′-CCCGAGGUCAAGUUCAACA-3′ (SEQ ID NO: 3172)AAT-1442 19 nt Target #3: 5′-CCCCGAGGUCAAGUUCAAC-3′ (SEQ ID NO: 3312)AAT-1443 19 nt Target #1: 5′-CGAGGUCAAGUUCAACAAA-3′ (SEQ ID NO: 3033)AAT-1443 19 nt Target #2: 5′-CCGAGGUCAAGUUCAACAA-3′ (SEQ ID NO: 3173)AAT-1443 19 nt Target #3: 5′-CCCGAGGUCAAGUUCAACA-3′ (SEQ ID NO: 3313)AAT-1444 19 nt Target #1: 5′-GAGGUCAAGUUCAACAAAC-3′ (SEQ ID NO: 3034)AAT-1444 19 nt Target #2: 5′-CGAGGUCAAGUUCAACAAA-3′ (SEQ ID NO: 3174)AAT-1444 19 nt Target #3: 5′-CCGAGGUCAAGUUCAACAA-3′ (SEQ ID NO: 3314)AAT-1445 19 nt Target #1: 5′-AGGUCAAGUUCAACAAACC-3′ (SEQ ID NO: 3035)AAT-1445 19 nt Target #2: 5′-GAGGUCAAGUUCAACAAAC-3′ (SEQ ID NO: 3175)AAT-1445 19 nt Target #3: 5′-CGAGGUCAAGUUCAACAAA-3′ (SEQ ID NO: 3315)AAT-1446 19 nt Target #1: 5′-GGUCAAGUUCAACAAACCC-3′ (SEQ ID NO: 3036)AAT-1446 19 nt Target #2: 5′-AGGUCAAGUUCAACAAACC-3′ (SEQ ID NO: 3176)AAT-1446 19 nt Target #3: 5′-GAGGUCAAGUUCAACAAAC-3′ (SEQ ID NO: 3316)AAT-1447 19 nt Target #1: 5′-GUCAAGUUCAACAAACCCU-3′ (SEQ ID NO: 3037)AAT-1447 19 nt Target #2: 5′-GGUCAAGUUCAACAAACCC-3′ (SEQ ID NO: 3177)AAT-1447 19 nt Target #3: 5′-AGGUCAAGUUCAACAAACC-3′ (SEQ ID NO: 3317)AAT-1448 19 nt Target #1: 5′-UCAAGUUCAACAAACCCUU-3′ (SEQ ID NO: 3038)AAT-1448 19 nt Target #2: 5′-GUCAAGUUCAACAAACCCU-3′ (SEQ ID NO: 3178)AAT-1448 19 nt Target #3: 5′-GGUCAAGUUCAACAAACCC-3′ (SEQ ID NO: 3318)AAT-1449 19 nt Target #1: 5′-CAAGUUCAACAAACCCUUU-3′ (SEQ ID NO: 3039)AAT-1449 19 nt Target #2: 5′-UCAAGUUCAACAAACCCUU-3′ (SEQ ID NO: 3179)AAT-1449 19 nt Target #3: 5′-GUCAAGUUCAACAAACCCU-3′ (SEQ ID NO: 3319)AAT-1450 19 nt Target #1: 5′-AAGUUCAACAAACCCUUUG-3′ (SEQ ID NO: 3040)AAT-1450 19 nt Target #2: 5′-CAAGUUCAACAAACCCUUU-3′ (SEQ ID NO: 3180)AAT-1450 19 nt Target #3: 5′-UCAAGUUCAACAAACCCUU-3′ (SEQ ID NO: 3320)AAT-1451 19 nt Target #1: 5′-AGUUCAACAAACCCUUUGU-3′ (SEQ ID NO: 3041)AAT-1451 19 nt Target #2: 5′-AAGUUCAACAAACCCUUUG-3′ (SEQ ID NO: 3181)AAT-1451 19 nt Target #3: 5′-CAAGUUCAACAAACCCUUU-3′ (SEQ ID NO: 3321)

TABLE 17 Other Human Anti-α-1 antitrypsin DsiRNA Agents (Asymmetries)5′-CCCCAGGGAGAUGCUGCCCAGAAga-3′ (SEQ ID NO: 3358)3′-UAGGGGUCCCUCUACGACGGGUCUUCU-5′ (SEQ ID NO: 3373)AAT-364 Target: 5′-ATCCCCAGGGAGATGCTGCCCAGAAGA-3′ (SEQ ID NO: 3388)5′-GCCUUUGCAAUGCUCUCCCUGGGga-3′ (SEQ ID NO: 3359)3′-GUCGGAAACGUUACGAGAGGGACCCCU-5′ (SEQ ID NO: 3374)AAT-535 Target: 5′-CAGCCTTTGCAATGCTCTCCCTGGGGA-3′ (SEQ ID NO: 3389)5′-GCAAUGCUCUCCCUGGGGACCAAgg-3′ (SEQ ID NO: 3360)3′-AACGUUACGAGAGGGACCCCUGGUUCC-5′ (SEQ ID NO: 3375)AAT-541 Target: 5′-TTGCAATGCTCTCCCTGGGGACCAAGG-3′ (SEQ ID NO: 3390)5′-GGGGACCAAGGCUGACACUCACGat-3′ (SEQ ID NO: 3361)3′-GACCCCUGGUUCCGACUGUGAGUGCUA-5′ (SEQ ID NO: 3376)AAT-555 Target: 5′-CTGGGGACCAAGGCTGACACTCACGAT-3′ (SEQ ID NO: 3391)5′-UCCUGGAGGGCCUGAAUUUCAACct-3′ (SEQ ID NO: 3362)3′-UUAGGACCUCCCGGACUUAAAGUUGGA-5′ (SEQ ID NO: 3377)AAT-584 Target: 5′-AATCCTGGAGGGCCTGAATTTCAACCT-3′ (SEQ ID NO: 3392)5′-CAGACAGCCAGCUCCAGCUGACCac-3′ (SEQ ID NO: 3363)3′-CGGUCUGUCGGUCGAGGUCGACUGGUG-5′ (SEQ ID NO: 3378)AAT-674 Target: 5′-GCCAGACAGCCAGCTCCAGCTGACCAC-3′ (SEQ ID NO: 3393)5′-AUCUUCUUUAAAGGCAAAUGGGAga-3′ (SEQ ID NO: 3364)3′-UGUAGAAGAAAUUUCCGUUUACCCUCU-5′ (SEQ ID NO: 3379)AAT-919 Target: 5′-ACATCTTCTTTAAAGGCAAATGGGAGA-3′ (SEQ ID NO: 3394)5′-UUAAAGGCAAAUGGGAGAGACCCtt-3′ (SEQ ID NO: 3365)3′-GAAAUUUCCGUUUACCCUCUCUGGGAA-5′ (SEQ ID NO: 3380)AAT-926 Target: 5′-CTTTAAAGGCAAATGGGAGAGACCCTT-3′ (SEQ ID NO: 3395)5′-UAAAGGCAAAUGGGAGAGACCCUtt-3′ (SEQ ID NO: 3366)3′-AAAUUUCCGUUUACCCUCUCUGGGAAA-5′ (SEQ ID NO: 3381)AAT-927 Target: 5′-TTTAAAGGCAAATGGGAGAGACCCTTT-3′ (SEQ ID NO: 3396)5′-AGAAGCUGUCCAGCUGGGUGCUGct-3′ (SEQ ID NO: 33 67)3′-AUUCUUCGACAGGUCGACCCACGACGA-5′ (SEQ ID NO: 3382)AAT-1055 Target: 5′-TAAGAAGCTGTCCAGCTGGGTGCTGCT-3′ (SEQ ID NO: 3397)5′-AUGCCACCGCCAUCUUCUUCCUGCC-3′ (SEQ ID NO: 3368)3′-GUUACGGUGGCGGUAGAAGAAGGACGG-5′ (SEQ ID NO: 3383)AAT-1097 Target: 5′-CAATGCCACCGCCATCTTCTTCCTGCC-3′ (SEQ ID NO: 3398)5′-GCCACCGCCAUCUUCUUCCUGCCtg-3′ (SEQ ID NO: 3369)3′-UACGGUGGCGGUAGAAGAAGGACGGAC-5′ (SEQ ID NO: 3384)AAT-1099 Target: 5′-ATGCCACCGCCATCTTCTTCCTGCCTG-3′ (SEQ ID NO: 3399)5′-AGGAGGCACCCCUGAAGCUCUCCaa-3′ (SEQ ID NO: 3370)3′-UCUCCUCCGUGGGGACUUCGAGAGGUU-5′ (SEQ ID NO: 3385)AAT-1325 Target: 5′-AGAGGAGGCACCCCTGAAGCTCTCCAA-3′ (SEQ ID NO: 3400)5′-AAGGCCGUGCAUAAGGCUGUGCUga-3′ (SEQ ID NO: 3371)3′-GGUUCCGGCACGUAUUCCGACACGACU-5′ (SEQ ID NO: 3386)AAT-1348 Target: 5′-CCAAGGCCGTGCATAAGGCTGTGCTGA-3′ (SEQ ID NO: 3401)5′-CCGUGCAUAAGGCUGUGCUGACCat-3′ (SEQ ID NO: 3372)3′-CCGGCACGUAUUCCGACACGACUGGUA-5′ (SEQ ID NO: 3387)AAT-1352 Target: 5′-GGCCGTGCATAAGGCTGTGCTGACCAT-3′ (SEQ ID NO: 3402)

TABLE 18Other Human Anti-α-1 antitrypsin DsiRNAs, Unmodified Duplexes (Asymmetries)5′-CCCCAGGGAGAUGCUGCCCAGAAGA-3′ (SEQ ID NO: 3403)3′-UAGGGGUCCCUCUACGACGGGUCUUCU-5′ (SEQ ID NO: 3373)AAT-364 Target: 5′-ATCCCCAGGGAGATGCTGCCCAGAAGA-3′ (SEQ ID NO: 3388)5′-GCCUUUGCAAUGCUCUCCCUGGGGA-3′ (SEQ ID NO: 3404)3′-GUCGGAAACGUUACGAGAGGGACCCCU-5′ (SEQ ID NO: 3374)AAT-535 Target: 5′-CAGCCTTTGCAATGCTCTCCCTGGGGA-3′ (SEQ ID NO: 3389)5′-GCAAUGCUCUCCCUGGGGACCAAGG-3′ (SEQ ID NO: 3405)3′-AACGUUACGAGAGGGACCCCUGGUUCC-5′ (SEQ ID NO: 3375)AAT-541 Target: 5′-TTGCAATGCTCTCCCTGGGGACCAAGG-3′ (SEQ ID NO: 3390)5′-GGGGACCAAGGCUGACACUCACGAU-3′ (SEQ ID NO: 3406)3′-GACCCCUGGUUCCGACUGUGAGUGCUA-5′ (SEQ ID NO: 3376)AAT-555 Target: 5′-CTGGGGACCAAGGCTGACACTCACGAT-3′ (SEQ ID NO: 3391)5′-UCCUGGAGGGCCUGAAUUUCAACCU-3′ (SEQ ID NO: 3407)3′-UUAGGACCUCCCGGACUUAAAGUUGGA-5′ (SEQ ID NO: 3377)AAT-584 Target: 5′-AATCCTGGAGGGCCTGAATTTCAACCT-3′ (SEQ ID NO: 3392)5′-CAGACAGCCAGCUCCAGCUGACCAC-3′ (SEQ ID NO: 3408)3′-CGGUCUGUCGGUCGAGGUCGACUGGUG-5′ (SEQ ID NO: 3378)AAT-674 Target: 5′-GCCAGACAGCCAGCTCCAGCTGACCAC-3′ (SEQ ID NO: 3393)5′-AUCUUCUUUAAAGGCAAAUGGGAGA-3′ (SEQ ID NO: 3409)3′-UGUAGAAGAAAUUUCCGUUUACCCUCU-5′ (SEQ ID NO: 3379)AAT-919 Target: 5′-ACATCTTCTTTAAAGGCAAATGGGAGA-3′ (SEQ ID NO: 3394)5′-UUAAAGGCAAAUGGGAGAGACCCUU-3′ (SEQ ID NO: 3410)3′-GAAAUUUCCGUUUACCCUCUCUGGGAA-5′ (SEQ ID NO: 3380)AAT-926 Target: 5′-CTTTAAAGGCAAATGGGAGAGACCCTT-3′ (SEQ ID NO: 3395)5′-UAAAGGCAAAUGGGAGAGACCCUUU-3′ (SEQ ID NO: 3411)3′-AAAUUUCCGUUUACCCUCUCUGGGAAA-5′ (SEQ ID NO: 3381)AAT-927 Target: 5′-TTTAAAGGCAAATGGGAGAGACCCTTT-3′ (SEQ ID NO: 3396)5′-AGAAGCUGUCCAGCUGGGUGCUGCU-3′ (SEQ ID NO: 3412)3′-AUUCUUCGACAGGUCGACCCACGACGA-5′ (SEQ ID NO: 3382)AAT-1055 Target: 5′-TAAGAAGCTGTCCAGCTGGGTGCTGCT-3′ (SEQ ID NO: 3397)5′-AUGCCACCGCCAUCUUCUUCCUGCC-3′ (SEQ ID NO: 3413)3′-GUUACGGUGGCGGUAGAAGAAGGACGG-5′ (SEQ ID NO: 3383)AAT-1097 Target: 5′-CAATGCCACCGCCATCTTCTTCCTGCC-3′ (SEQ ID NO: 3398)5′-GCCACCGCCAUCUUCUUCCUGCCUG-3′ (SEQ ID NO: 3414)3′-UACGGUGGCGGUAGAAGAAGGACGGAC-5′ (SEQ ID NO: 3384)AAT-1099 Target: 5′-ATGCCACCGCCATCTTCTTCCTGCCTG-3′ (SEQ ID NO: 3399)5′-AGGAGGCACCCCUGAAGCUCUCCAA-3′ (SEQ ID NO: 3415)3′-UCUCCUCCGUGGGGACUUCGAGAGGUU-5′ (SEQ ID NO: 3385)AAT-1325 Target: 5′-AGAGGAGGCACCCCTGAAGCTCTCCAA-3′ (SEQ ID NO: 3400)5′-AAGGCCGUGCAUAAGGCUGUGCUGA-3′ (SEQ ID NO: 3416)3′-GGUUCCGGCACGUAUUCCGACACGACU-5′ (SEQ ID NO: 3386)AAT-1348 Target: 5′-CCAAGGCCGTGCATAAGGCTGTGCTGA-3′ (SEQ ID NO: 3401)5′-CCGUGCAUAAGGCUGUGCUGACCAU-3′ (SEQ ID NO: 3417)3′-CCGGCACGUAUUCCGACACGACUGGUA-5′ (SEQ ID NO: 3387)AAT-1352 Target: 5′-GGCCGTGCATAAGGCTGTGCTGACCAT-3′ (SEQ ID NO: 3402)

TABLE 19 Other DsiRNA Target Sequences (21 mers) in α-1 antitrypsin mRNAAAT-364 21 nt Target: 5′-AUCCCCAGGGAGAUGCUGCCC-3′ (SEQ ID NO: 3418)AAT-535 21 nt Target: 5′-CAGCCUUUGCAAUGCUCUCCC-3′ (SEQ ID NO: 3419)AAT-541 21 nt Target: 5′-UUGCAAUGCUCUCCCUGGGGA-3′ (SEQ ID NO: 3420)AAT-555 21 nt Target: 5′-CUGGGGACCAAGGCUGACACU-3′ (SEQ ID NO: 3421)AAT-584 21 nt Target: 5′-AAUCCUGGAGGGCCUGAAUUU-3′ (SEQ ID NO: 3422)AAT-674 21 nt Target: 5′-GCCAGACAGCCAGCUCCAGCU-3′ (SEQ ID NO: 3423)AAT-919 21 nt Target: 5′-ACAUCUUCUUUAAAGGCAAAU-3′ (SEQ ID NO: 3424)AAT-926 21 nt Target: 5′-CUUUAAAGGCAAAUGGGAGAG-3′ (SEQ ID NO: 3425)AAT-927 21 nt Target: 5′-UUUAAAGGCAAAUGGGAGAGA-3′ (SEQ ID NO: 3426)AAT-1055 21 nt Target: 5′-UAAGAAGCUGUCCAGCUGGGU-3′ (SEQ ID NO: 3427)AAT-1097 21 nt Target: 5′-CAAUGCCACCGCCAUCUUCUU-3′ (SEQ ID NO: 3428)AAT-1099 21 nt Target: 5′-AUGCCACCGCCAUCUUCUUCC-3′ (SEQ ID NO: 3429)AAT-1325 21 nt Target: 5′-AGAGGAGGCACCCCUGAAGCU-3′ (SEQ ID NO: 3430)AAT-1348 21 nt Target: 5′-CCAAGGCCGUGCAUAAGGCUG-3′ (SEQ ID NO: 3431)AAT-1352 21 nt Target: 5′-GGCCGUGCAUAAGGCUGUGCU-3′ (SEQ ID NO: 3432)

TABLE 20 Other Human Anti-α-1 antitrypsin “Blunt/Blunt” DsiRNAs5′-AUCCCCAGGGAGAUGCUGCCCAGAAGA-3′ (SEQ ID NO: 3433)3′-UAGGGGUCCCUCUACGACGGGUCUUCU-5′ (SEQ ID NO: 3373)AAT-364 Target: 5′-ATCCCCAGGGAGATGCTGCCCAGAAGA-3′ (SEQ ID NO: 3388)5′-CAGCCUUUGCAAUGCUCUCCCUGGGGA-3′ (SEQ ID NO: 3434)3′-GUCGGAAACGUUACGAGAGGGACCCCU-5′ (SEQ ID NO: 3374)AAT-535 Target: 5′-CAGCCTTTGCAATGCTCTCCCTGGGGA-3′ (SEQ ID NO: 3389)5′-UUGCAAUGCUCUCCCUGGGGACCAAGG-3′ (SEQ ID NO: 3435)3′-AACGUUACGAGAGGGACCCCUGGUUCC-5′ (SEQ ID NO: 3375)AAT-541 Target: 5′-TTGCAATGCTCTCCCTGGGGACCAAGG-3′ (SEQ ID NO: 3390)5′-CUGGGGACCAAGGCUGACACUCACGAU-3′ (SEQ ID NO: 3436)3′-GACCCCUGGUUCCGACUGUGAGUGCUA-5′ (SEQ ID NO: 3376)AAT-555 Target: 5′-CTGGGGACCAAGGCTGACACTCACGAT-3′ (SEQ ID NO: 3391)5′-AAUCCUGGAGGGCCUGAAUUUCAACCU-3′ (SEQ ID NO: 3437)3′-UUAGGACCUCCCGGACUUAAAGUUGGA-5′ (SEQ ID NO: 3377)AAT-584 Target: 5′-AATCCTGGAGGGCCTGAATTTCAACCT-3′ (SEQ ID NO: 3392)5′-GCCAGACAGCCAGCUCCAGCUGACCAC-3′ (SEQ ID NO: 3438)3′-CGGUCUGUCGGUCGAGGUCGACUGGUG-5′ (SEQ ID NO: 3378)AAT-674 Target: 5′-GCCAGACAGCCAGCTCCAGCTGACCAC-3′ (SEQ ID NO: 3393)5′-ACAUCUUCUUUAAAGGCAAAUGGGAGA-3′ (SEQ ID NO: 3439)3′-UGUAGAAGAAAUUUCCGUUUACCCUCU-5′ (SEQ ID NO: 3379)AAT-919 Target: 5′-ACATCTTCTTTAAAGGCAAATGGGAGA-3′ (SEQ ID NO: 3394)5′-CUUUAAAGGCAAAUGGGAGAGACCCUU-3′ (SEQ ID NO: 3440)3′-GAAAUUUCCGUUUACCCUCUCUGGGAA-5′ (SEQ ID NO: 3380)AAT-926 Target: 5′-CTTTAAAGGCAAATGGGAGAGACCCTT-3′ (SEQ ID NO: 3395)5′-UUUAAAGGCAAAUGGGAGAGACCCUUU-3′ (SEQ ID NO: 3441)3′-AAAUUUCCGUUUACCCUCUCUGGGAAA-5′ (SEQ ID NO: 3381)AAT-927 Target: 5′-TTTAAAGGCAAATGGGAGAGACCCTTT-3′ (SEQ ID NO: 3396)5′-UAAGAAGCUGUCCAGCUGGGUGCUGCU-3′ (SEQ ID NO: 3442)3′-AUUCUUCGACAGGUCGACCCACGACGA-5′ (SEQ ID NO: 3382)AAT-1055 Target: 5′-TAAGAAGCTGTCCAGCTGGGTGCTGCT-3′ (SEQ ID NO: 3397)5′-CAAUGCCACCGCCAUCUUCUUCCUGCC-3′ (SEQ ID NO: 3443)3′-GUUACGGUGGCGGUAGAAGAAGGACGG-5′ (SEQ ID NO: 3383)AAT-1097 Target: 5′-CAATGCCACCGCCATCTTCTTCCTGCC-3′ (SEQ ID NO: 3398)5′-AUGCCACCGCCAUCUUCUUCCUGCCUG-3′ (SEQ ID NO: 3444)3′-UACGGUGGCGGUAGAAGAAGGACGGAC-5′ (SEQ ID NO: 3384)AAT-1099 Target: 5′-ATGCCACCGCCATCTTCTTCCTGCCTG-3′ (SEQ ID NO: 3399)5′-AGAGGAGGCACCCCUGAAGCUCUCCAA-3′ (SEQ ID NO: 3445)3′-UCUCCUCCGUGGGGACUUCGAGAGGUU-5′ (SEQ ID NO: 3385)AAT-1325 Target: 5′-AGAGGAGGCACCCCTGAAGCTCTCCAA-3′ (SEQ ID NO: 3400)5′-CCAAGGCCGUGCAUAAGGCUGUGCUGA-3′ (SEQ ID NO: 3446)3′-GGUUCCGGCACGUAUUCCGACACGACU-5′ (SEQ ID NO: 3386)AAT-1348 Target: 5′-CCAAGGCCGTGCATAAGGCTGTGCTGA-3′ (SEQ ID NO: 3401)5′-GGCCGUGCAUAAGGCUGUGCUGACCAU-3′ (SEQ ID NO: 3447)3′-CCGGCACGUAUUCCGACACGACUGGUA-5′ (SEQ ID NO: 3387)AAT-1352 Target: 5′-GGCCGTGCATAAGGCTGTGCTGACCAT-3′ (SEQ ID NO: 3402)

TABLE 21Other DsiRNA Component 19 Nucleotide Target Sequences in a-1 antitrypsinmRNAAAT-364 19 nt Target #1: 5′-CCCCAGGGAGAUGCUGCCC-3′ (SEQ ID NO: 3448)AAT-364 19 nt Target #2: 5′-UCCCCAGGGAGAUGCUGCC-3′ (SEQ ID NO: 3463)AAT-364 19 nt Target #3: 5′-AUCCCCAGGGAGAUGCUGC-3′ (SEQ ID NO: 3478)AAT-535 19 nt Target #1: 5′-GCCUUUGCAAUGCUCUCCC-3′ (SEQ ID NO: 3449)AAT-535 19 nt Target #2: 5′-AGCCUUUGCAAUGCUCUCC-3′ (SEQ ID NO: 3464)AAT-535 19 nt Target #3: 5′-CAGCCUUUGCAAUGCUCUC-3′ (SEQ ID NO: 3479)AAT-541 19 nt Target #1: 5′-GCAAUGCUCUCCCUGGGGA-3′ (SEQ ID NO: 3450)AAT-541 19 nt Target #2: 5′-UGCAAUGCUCUCCCUGGGG-3′ (SEQ ID NO: 3465)AAT-541 19 nt Target #3: 5′-UUGCAAUGCUCUCCCUGGG-3′ (SEQ ID NO: 3480)AAT-555 19 nt Target #1: 5′-GGGGACCAAGGCUGACACU-3′ (SEQ ID NO: 3451)AAT-555 19 nt Target #2: 5′-UGGGGACCAAGGCUGACAC-3′ (SEQ ID NO: 3466)AAT-555 19 nt Target #3: 5′-CUGGGGACCAAGGCUGACA-3′ (SEQ ID NO: 3481)AAT-584 19 nt Target #1: 5′-UCCUGGAGGGCCUGAAUUU-3′ (SEQ ID NO: 3452)AAT-584 19 nt Target #2: 5′-AUCCUGGAGGGCCUGAAUU-3′ (SEQ ID NO: 3467)AAT-584 19 nt Target #3: 5′-AAUCCUGGAGGGCCUGAAU-3′ (SEQ ID NO: 3482)AAT-674 19 nt Target #1: 5′-CAGACAGCCAGCUCCAGCU-3′ (SEQ ID NO: 3453)AAT-674 19 nt Target #2: 5′-CCAGACAGCCAGCUCCAGC-3′ (SEQ ID NO: 3468)AAT-674 19 nt Target #3: 5′-GCCAGACAGCCAGCUCCAG-3′ (SEQ ID NO: 3483)AAT-919 19 nt Target #1: 5′-AUCUUCUUUAAAGGCAAAU-3′ (SEQ ID NO: 3454)AAT-919 19 nt Target #2: 5′-CAUCUUCUUUAAAGGCAAA-3′ (SEQ ID NO: 3469)AAT-919 19 nt Target #3: 5′-ACAUCUUCUUUAAAGGCAA-3′ (SEQ ID NO: 3484)AAT-926 19 nt Target #1: 5′-UUAAAGGCAAAUGGGAGAG-3′ (SEQ ID NO: 3455)AAT-926 19 nt Target #2: 5′-UUUAAAGGCAAAUGGGAGA-3′ (SEQ ID NO: 3470)AAT-926 19 nt Target #3: 5′-CUUUAAAGGCAAAUGGGAG-3′ (SEQ ID NO: 3485)AAT-927 19 nt Target #1: 5′-UAAAGGCAAAUGGGAGAGA-3′ (SEQ ID NO: 3456)AAT-927 19 nt Target #2: 5′-UUAAAGGCAAAUGGGAGAG-3′ (SEQ ID NO: 3471)AAT-927 19 nt Target #3: 5′-UUUAAAGGCAAAUGGGAGA-3′ (SEQ ID NO: 3486)AAT-1055 19 nt Target #1: 5′-AGAAGCUGUCCAGCUGGGU-3′ (SEQ ID NO: 3457)AAT-1055 19 nt Target #2: 5′-AAGAAGCUGUCCAGCUGGG-3′ (SEQ ID NO: 3472)AAT-1055 19 nt Target #3: 5′-UAAGAAGCUGUCCAGCUGG-3′ (SEQ ID NO: 3487)AAT-1097 19 nt Target #1: 5′-AUGCCACCGCCAUCUUCUU-3′ (SEQ ID NO: 3458)AAT-1097 19 nt Target #2: 5′-AAUGCCACCGCCAUCUUCU-3′ (SEQ ID NO: 3473)AAT-1097 19 nt Target #3: 5′-CAAUGCCACCGCCAUCUUC-3′ (SEQ ID NO: 3488)AAT-1099 19 nt Target #1: 5′-GCCACCGCCAUCUUCUUCC-3′ (SEQ ID NO: 3459)AAT-1099 19 nt Target #2: 5′-UGCCACCGCCAUCUUCUUC-3′ (SEQ ID NO: 3474)AAT-1099 19 nt Target #3: 5′-AUGCCACCGCCAUCUUCUU-3′ (SEQ ID NO: 3489)AAT-1325 19 nt Target #1: 5′-AGGAGGCACCCCUGAAGCU-3′ (SEQ ID NO: 3460)AAT-1325 19 nt Target #2: 5′-GAGGAGGCACCCCUGAAGC-3′ (SEQ ID NO: 3475)AAT-1325 19 nt Target #3: 5′-AGAGGAGGCACCCCUGAAG-3′ (SEQ ID NO: 3490)AAT-1348 19 nt Target #1: 5′-AAGGCCGUGCAUAAGGCUG-3′ (SEQ ID NO: 3461)AAT-1348 19 nt Target #2: 5′-CAAGGCCGUGCAUAAGGCU-3′ (SEQ ID NO: 3476)AAT-1348 19 nt Target #3: 5′-CCAAGGCCGUGCAUAAGGC-3′ (SEQ ID NO: 3491)AAT-1352 19 nt Target #1: 5′-CCGUGCAUAAGGCUGUGCU-3′ (SEQ ID NO: 3462)AAT-1352 19 nt Target #2: 5′-GCCGUGCAUAAGGCUGUGC-3′ (SEQ ID NO: 3477)AAT-1352 19 nt Target #3: 5′-GGCCGUGCAUAAGGCUGUG-3′ (SEQ ID NO: 3492)

Within Tables 2, 3, 5, 7, 8, 10, 12, 13, 15, 17, 18 and 20 above,underlined residues indicate 2′-O-methyl residues, UPPER CASE indicatesribonucleotides, and lower case denotes deoxyribonucleotides. The DsiRNAagents of Tables 2-3, 7-8, 12-13 and 17-18 above are 25/27mer agentspossessing a blunt end. The structures and/or modification patterning ofthe agents of Tables 2-3, 7-8, 12-13 and 17-18 above can be readilyadapted to the above generic sequence structures, e.g., the 3′ overhangof the second strand can be extended or contracted, 2′-O-methylation ofthe second strand can be expanded towards the 5′ end of the secondstrand, optionally at alternating sites, etc. Such further modificationsare optional, as 25/27mer DsiRNAs with such modifications can also bereadily designed from the above DsiRNA agents and are also expected tobe functional inhibitors of α-1 antitrypsin expression. Similarly, the27mer “blunt/blunt” DsiRNA structures and/or modification patterns ofthe agents of Tables 5, 10, 15 and 20 above can also be readily adaptedto the above generic sequence structures, e.g., for application ofmodification patterning of the antisense strand to such structuresand/or adaptation of such sequences to the above generic structures.

In certain embodiments, 27mer DsiRNAs possessing independent strandlengths each of 27 nucleotides are designed and synthesized fortargeting of the same sites within the α-1 antitrypsin transcript as theasymmetric “25/27” structures shown in Tables 2-3, 7-8, 12-13 and 17-18herein. Exemplary “27/27” DsiRNAs are optionally designed with a“blunt/blunt” structure as shown for the DsiRNAs of Tables 5, 10, 15 and20 above.

In certain embodiments, the dsRNA agents of the invention require, e.g.,at least 19, at least 20, at least 21, at least 22, at least 23, atleast 24, at least 25 or at least 26 residues of the first strand to becomplementary to corresponding residues of the second strand. In certainrelated embodiments, these first strand residues complementary tocorresponding residues of the second strand are optionally consecutiveresidues.

In certain DsiRNAmm (“DsiRNA mismatch”) embodiments of the instantinvention, mismatched base pairs are located within a “mismatch-tolerantregion” which is defined herein with respect to the location of theprojected Ago2 cut site of the corresponding target nucleic acid. Themismatch tolerant region is located “upstream of” the projected Ago2 cutsite of the target strand. “Upstream” in this context will be understoodas the 5′-most portion of the DsiRNAmm duplex, where 5′ refers to theorientation of the sense strand of the DsiRNA duplex. Therefore, themismatch tolerant region is upstream of the base on the sense(passenger) strand that corresponds to the projected Ago2 cut site ofthe target nucleic acid (see FIG. 1 ); alternatively, when referring tothe antisense (guide) strand of the DsiRNAmm, the mismatch tolerantregion can also be described as positioned downstream of the base thatis complementary to the projected Ago2 cut site of the target nucleicacid, that is, the 3′-most portion of the antisense strand of theDsiRNAmm (where position 1 of the antisense strand is the 5′ terminalnucleotide of the antisense strand, see FIG. 1 ).

In one embodiment, for example with numbering as depicted in FIG. 1 ,the mismatch tolerant region is positioned between and including basepairs 3-9 when numbered from the nucleotide starting at the 5′ end ofthe sense strand of the duplex. Therefore, a DsiRNAmm of the inventionpossesses a single mismatched base pair at any one of positions 3, 4, 5,6, 7, 8 or 9 of the sense strand of a right-hand extended DsiRNA (whereposition 1 is the 5′ terminal nucleotide of the sense strand andposition 9 is the nucleotide residue of the sense strand that isimmediately 5′ of the projected Ago2 cut site of the target α-1antitrypsin RNA sequence corresponding to the sense strand sequence). Incertain embodiments, for a DsiRNAmm that possesses a mismatched basepair nucleotide at any of positions 3, 4, 5, 6, 7, 8 or 9 of the sensestrand, the corresponding mismatched base pair nucleotide of theantisense strand not only forms a mismatched base pair with the DsiRNAmmsense strand sequence, but also forms a mismatched base pair with aDsiRNAmm target α-1 antitrypsin RNA sequence (thus, complementaritybetween the antisense strand sequence and the sense strand sequence isdisrupted at the mismatched base pair within the DsiRNAmm, andcomplementarity is similarly disrupted between the antisense strandsequence of the DsiRNAmm and the target α-1 antitrypsin RNA sequence).In alternative embodiments, the mismatch base pair nucleotide of theantisense strand of a DsiRNAmm only form a mismatched base pair with acorresponding nucleotide of the sense strand sequence of the DsiRNAmm,yet base pairs with its corresponding target α-1 antitrypsin RNAsequence nucleotide (thus, complementarity between the antisense strandsequence and the sense strand sequence is disrupted at the mismatchedbase pair within the DsiRNAmm, yet complementarity is maintained betweenthe antisense strand sequence of the DsiRNAmm and the target α-1antitrypsin RNA sequence).

A DsiRNAmm of the invention that possesses a single mismatched base pairwithin the mismatch-tolerant region (mismatch region) as described above(e.g., a DsiRNAmm harboring a mismatched nucleotide residue at any oneof positions 3, 4, 5, 6, 7, 8 or 9 of the sense strand) can furtherinclude one, two or even three additional mismatched base pairs. Inpreferred embodiments, these one, two or three additional mismatchedbase pairs of the DsiRNAmm occur at position(s) 3, 4, 5, 6, 7, 8 and/or9 of the sense strand (and at corresponding residues of the antisensestrand). In one embodiment where one additional mismatched base pair ispresent within a DsiRNAmm, the two mismatched base pairs of the sensestrand can occur, e.g., at nucleotides of both position 4 and position 6of the sense strand (with mismatch also occurring at correspondingnucleotide residues of the antisense strand).

In DsiRNAmm agents possessing two mismatched base pairs, mismatches canoccur consecutively (e.g., at consecutive positions along the sensestrand nucleotide sequence). Alternatively, nucleotides of the sensestrand that form mismatched base pairs with the antisense strandsequence can be interspersed by nucleotides that base pair with theantisense strand sequence (e.g., for a DsiRNAmm possessing mismatchednucleotides at positions 3 and 6, but not at positions 4 and 5, themismatched residues of sense strand positions 3 and 6 are interspersedby two nucleotides that form matched base pairs with correspondingresidues of the antisense strand). For example, two residues of thesense strand (located within the mismatch-tolerant region of the sensestrand) that form mismatched base pairs with the corresponding antisensestrand sequence can occur with zero, one, two, three, four or fivematched base pairs located between these mismatched base pairs.

For certain DsiRNAmm agents possessing three mismatched base pairs,mismatches can occur consecutively (e.g., in a triplet along the sensestrand nucleotide sequence). Alternatively, nucleotides of the sensestrand that form mismatched base pairs with the antisense strandsequence can be interspersed by nucleotides that form matched base pairswith the antisense strand sequence (e.g., for a DsiRNAmm possessingmismatched nucleotides at positions 3, 4 and 8, but not at positions 5,6 and 7, the mismatched residues of sense strand positions 3 and 4 areadjacent to one another, while the mismatched residues of sense strandpositions 4 and 8 are interspersed by three nucleotides that formmatched base pairs with corresponding residues of the antisense strand).For example, three residues of the sense strand (located within themismatch-tolerant region of the sense strand) that form mismatched basepairs with the corresponding antisense strand sequence can occur withzero, one, two, three or four matched base pairs located between any twoof these mismatched base pairs.

For certain DsiRNAmm agents possessing four mismatched base pairs,mismatches can occur consecutively (e.g., in a quadruplet along thesense strand nucleotide sequence). Alternatively, nucleotides of thesense strand that form mismatched base pairs with the antisense strandsequence can be interspersed by nucleotides that form matched base pairswith the antisense strand sequence (e.g., for a DsiRNAmm possessingmismatched nucleotides at positions 3, 5, 7 and 8, but not at positions4 and 6, the mismatched residues of sense strand positions 7 and 8 areadjacent to one another, while the mismatched residues of sense strandpositions 3 and 5 are interspersed by one nucleotide that forms amatched base pair with the corresponding residue of the antisensestrand—similarly, the mismatched residues of sense strand positions 5and 7 are also interspersed by one nucleotide that forms a matched basepair with the corresponding residue of the antisense strand). Forexample, four residues of the sense strand (located within themismatch-tolerant region of the sense strand) that form mismatched basepairs with the corresponding antisense strand sequence can occur withzero, one, two or three matched base pairs located between any two ofthese mismatched base pairs.

In another embodiment, for example with numbering also as depicted inFIG. 1 , a DsiRNAmm of the invention comprises a mismatch tolerantregion which possesses a single mismatched base pair nucleotide at anyone of positions 17, 18, 19, 20, 21, 22 or 23 of the antisense strand ofthe DsiRNA (where position 1 is the 5′ terminal nucleotide of theantisense strand and position 17 is the nucleotide residue of theantisense strand that is immediately 3′ (downstream) in the antisensestrand of the projected Ago2 cut site of the target α-1 antitrypsin RNAsequence sufficiently complementary to the antisense strand sequence).In certain embodiments, for a DsiRNAmm that possesses a mismatched basepair nucleotide at any of positions 17, 18, 19, 20, 21, 22 or 23 of theantisense strand with respect to the sense strand of the DsiRNAmm, themismatched base pair nucleotide of the antisense strand not only forms amismatched base pair with the DsiRNAmm sense strand sequence, but alsoforms a mismatched base pair with a DsiRNAmm target α-1 antitrypsin RNAsequence (thus, complementarity between the antisense strand sequenceand the sense strand sequence is disrupted at the mismatched base pairwithin the DsiRNAmm, and complementarity is similarly disrupted betweenthe antisense strand sequence of the DsiRNAmm and the target α-1antitrypsin RNA sequence). In alternative embodiments, the mismatch basepair nucleotide of the antisense strand of a DsiRNAmm only forms amismatched base pair with a corresponding nucleotide of the sense strandsequence of the DsiRNAmm, yet base pairs with its corresponding targetα-1 antitrypsin RNA sequence nucleotide (thus, complementarity betweenthe antisense strand sequence and the sense strand sequence is disruptedat the mismatched base pair within the DsiRNAmm, yet complementarity ismaintained between the antisense strand sequence of the DsiRNAmm and thetarget α-1 antitrypsin RNA sequence).

A DsiRNAmm of the invention that possesses a single mismatched base pairwithin the mismatch-tolerant region as described above (e.g., a DsiRNAmmharboring a mismatched nucleotide residue at positions 17, 18, 19, 20,21, 22 or 23 of the antisense strand) can further include one, two oreven three additional mismatched base pairs. In preferred embodiments,these one, two or three additional mismatched base pairs of the DsiRNAmmoccur at position(s) 17, 18, 19, 20, 21, 22 and/or 23 of the antisensestrand (and at corresponding residues of the sense strand). In oneembodiment where one additional mismatched base pair is present within aDsiRNAmm, the two mismatched base pairs of the antisense strand canoccur, e.g., at nucleotides of both position 18 and position 20 of theantisense strand (with mismatch also occurring at correspondingnucleotide residues of the sense strand).

In DsiRNAmm agents possessing two mismatched base pairs, mismatches canoccur consecutively (e.g., at consecutive positions along the antisensestrand nucleotide sequence). Alternatively, nucleotides of the antisensestrand that form mismatched base pairs with the sense strand sequencecan be interspersed by nucleotides that base pair with the sense strandsequence (e.g., for a DsiRNAmm possessing mismatched nucleotides atpositions 17 and 20, but not at positions 18 and 19, the mismatchedresidues of antisense strand positions 17 and 20 are interspersed by twonucleotides that form matched base pairs with corresponding residues ofthe sense strand). For example, two residues of the antisense strand(located within the mismatch-tolerant region of the sense strand) thatform mismatched base pairs with the corresponding sense strand sequencecan occur with zero, one, two, three, four, five, six or seven matchedbase pairs located between these mismatched base pairs.

For certain DsiRNAmm agents possessing three mismatched base pairs,mismatches can occur consecutively (e.g., in a triplet along theantisense strand nucleotide sequence). Alternatively, nucleotides of theantisense strand that form mismatched base pairs with the sense strandsequence can be interspersed by nucleotides that form matched base pairswith the sense strand sequence (e.g., for a DsiRNAmm possessingmismatched nucleotides at positions 17, 18 and 22, but not at positions19, 20 and 21, the mismatched residues of antisense strand positions 17and 18 are adjacent to one another, while the mismatched residues ofantisense strand positions 18 and 122 are interspersed by threenucleotides that form matched base pairs with corresponding residues ofthe sense strand). For example, three residues of the antisense strand(located within the mismatch-tolerant region of the antisense strand)that form mismatched base pairs with the corresponding sense strandsequence can occur with zero, one, two, three, four, five or six matchedbase pairs located between any two of these mismatched base pairs.

For certain DsiRNAmm agents possessing four mismatched base pairs,mismatches can occur consecutively (e.g., in a quadruplet along theantisense strand nucleotide sequence). Alternatively, nucleotides of theantisense strand that form mismatched base pairs with the sense strandsequence can be interspersed by nucleotides that form matched base pairswith the sense strand sequence (e.g., for a DsiRNAmm possessingmismatched nucleotides at positions 18, 20, 22 and 23, but not atpositions 19 and 21, the mismatched residues of antisense strandpositions 22 and 23 are adjacent to one another, while the mismatchedresidues of antisense strand positions 18 and 20 are interspersed by onenucleotide that forms a matched base pair with the corresponding residueof the sense strand—similarly, the the mismatched residues of antisensestrand positions 20 and 22 are also interspersed by one nucleotide thatforms a matched base pair with the corresponding residue of the sensestrand). For example, four residues of the antisense strand (locatedwithin the mismatch-tolerant region of the antisense strand) that formmismatched base pairs with the corresponding sense strand sequence canoccur with zero, one, two, three, four or five matched base pairslocated between any two of these mismatched base pairs.

For reasons of clarity, the location(s) of mismatched nucleotideresidues within the above DsiRNAmm agents are numbered in reference tothe 5′ terminal residue of either sense or antisense strands of theDsiRNAmm. The numbering of positions located within themismatch-tolerant region (mismatch region) of the antisense strand canshift with variations in the proximity of the 5′ terminus of the senseor antisense strand to the projected Ago2 cleavage site. Thus, thelocation(s) of preferred mismatch sites within either antisense strandor sense strand can also be identified as the permissible proximity ofsuch mismatches to the projected Ago2 cut site. Accordingly, in onepreferred embodiment, the position of a mismatch nucleotide of the sensestrand of a DsiRNAmm is the nucleotide residue of the sense strand thatis located immediately 5′ (upstream) of the projected Ago2 cleavage siteof the corresponding target α-1 antitrypsin RNA sequence. In otherpreferred embodiments, a mismatch nucleotide of the sense strand of aDsiRNAmm is positioned at the nucleotide residue of the sense strandthat is located two nucleotides 5′ (upstream) of the projected Ago2cleavage site, three nucleotides 5′ (upstream) of the projected Ago2cleavage site, four nucleotides 5′ (upstream) of the projected Ago2cleavage site, five nucleotides 5′ (upstream) of the projected Ago2cleavage site, six nucleotides 5′ (upstream) of the projected Ago2cleavage site, seven nucleotides 5′ (upstream) of the projected Ago2cleavage site, eight nucleotides 5′ (upstream) of the projected Ago2cleavage site, or nine nucleotides 5′ (upstream) of the projected Ago2cleavage site.

Exemplary single mismatch-containing 25/27mer DsiRNAs (DsiRNAmm) includethe following structures (such mismatch-containing structures may alsobe incorporated into other exemplary DsiRNA structures shown herein).

  5′-XX^(M)XXXXXXXXXXXXXXXXXXXXDD-3′3′-XXXX_(M)XXXXXXXXXXXXXXXXXXXXXX-5′  5′-XXX^(M)XXXXXXXXXXXXXXXXXXXDD-3′3′-XXXXX_(M)XXXXXXXXXXXXXXXXXXXXX-5′  5′-XXXX^(M)XXXXXXXXXXXXXXXXXXDD-3′3′-XXXXXX_(M)XXXXXXXXXXXXXXXXXXXX-5′  5′-XXXXX^(M)XXXXXXXXXXXXXXXXXDD-3′3′-XXXXXXX_(M)XXXXXXXXXXXXXXXXXXX-5′  5′-XXXXXX^(M)XXXXXXXXXXXXXXXXDD-3′3′-XXXXXXXX_(M)XXXXXXXXXXXXXXXXXX-5′  5′-XXXXXXX^(M)XXXXXXXXXXXXXXXDD-3′3′-XXXXXXXXX_(M)XXXXXXXXXXXXXXXXX-5′  5′-XXXXXXXX^(M)XXXXXXXXXXXXXXDD-3′3′-XXXXXXXXXX_(M)XXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “D”=DNA and “M”=Nucleic acid residues (RNA, DNA ornon-natural or modified nucleic acids) that do not base pair (hydrogenbond) with corresponding “M” residues of otherwise complementary strandwhen strands are annealed. Any of the residues of such agents canoptionally be 2′-O-methyl RNA monomers—alternating positioning of2′-O-methyl RNA monomers that commences from the 3′-terminal residue ofthe bottom (second) strand, as shown above, can also be used in theabove DsiRNAmm agents. For the above mismatch structures, the top strandis the sense strand, and the bottom strand is the antisense strand.

In certain embodiments, a DsiRNA of the invention can contain mismatchesthat exist in reference to the target α-1 antitrypsin RNA sequence yetdo not necessarily exist as mismatched base pairs within the two strandsof the DsiRNA—thus, a DsiRNA can possess perfect complementarity betweenfirst and second strands of a DsiRNA, yet still possess mismatchedresidues in reference to a target α-1 antitrypsin RNA (which, in certainembodiments, may be advantageous in promoting efficacy and/or potencyand/or duration of effect). In certain embodiments, where mismatchesoccur between antisense strand and target α-1 antitrypsin RNA sequence,the position of a mismatch is located within the antisense strand at aposition(s) that corresponds to a sequence of the sense strand located5′ of the projected Ago2 cut site of the target region—e.g., antisensestrand residue(s) positioned within the antisense strand to the 3′ ofthe antisense residue which is complementary to the projected Ago2 cutsite of the target sequence.

Exemplary 25/27mer DsiRNAs that harbor a single mismatched residue inreference to target sequences include the following structures.

Target RNA Sequence: 5′-...AXXXXXXXXXXXXXXXXXXXX...-3′DsiRNAmm Sense Strand: 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′DsiRNAmm Antisense Strand: 3′-EXXXXXXXXXXXXXXXXXXXXXXXXXX-5′Target RNA Sequence: 5′-...XAXXXXXXXXXXXXXXXXXXX...-3′DsiRNAmm Sense Strand: 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′DsiRNAmm Antisense Strand: 3′-XEXXXXXXXXXXXXXXXXXXXXXXXXX-5′Target RNA Sequence:5′-...AXXXXXXXXXXXXXXXXXX...-3′DsiRNAmm Sense Strand: 5′-BXXXXXXXXXXXXXXXXXXXXXXDD-3′DsiRNAmm Antisense Strand: 3′-XXEXXXXXXXXXXXXXXXXXXXXXXXX-5′Target RNA Sequence:5′-...XAXXXXXXXXXXXXXXXXX...-3′DsiRNAmm Sense Strand: 5′-XBXXXXXXXXXXXXXXXXXXXXXDD-3′DsiRNAmm Antisense Strand: 3′-XXXEXXXXXXXXXXXXXXXXXXXXXXX-5′Target RNA Sequence:5′-...XXAXXXXXXXXXXXXXXXX...-3′DsiRNAmm Sense Strand: 5′-XXBXXXXXXXXXXXXXXXXXXXXDD-3′DsiRNAmm Antisense Strand: 3′-XXXXEXXXXXXXXXXXXXXXXXXXXXX-5′Target RNA Sequence:5′-...XXXAXXXXXXXXXXXXXXX...-3′DsiRNAmm Sense Strand: 5′-XXXBXXXXXXXXXXXXXXXXXXXDD-3′DsiRNAmm Antisense Strand: 3′-XXXXXEXXXXXXXXXXXXXXXXXXXXX-5′Target RNA Sequence:5′-...XXXXAXXXXXXXXXXXXXX...-3′DsiRNAmm Sense Strand: 5′-XXXXBXXXXXXXXXXXXXXXXXXDD-3′DsiRNAmm Antisense Strand: 3′-XXXXXXEXXXXXXXXXXXXXXXXXXXX-5′Target RNA Sequence:5′-...XXXXXAXXXXXXXXXXXXX...-3′DsiRNAmm Sense Strand: 5′-XXXXXBXXXXXXXXXXXXXXXXXDD-3′DsiRNAmm Antisense Strand: 3′-XXXXXXXEXXXXXXXXXXXXXXXXXXX-5′Target RNA Sequence:5′-...XXXXXXAXXXXXXXXXXXX...-3′DsiRNAmm Sense Strand: 5′-XXXXXXBXXXXXXXXXXXXXXXXDD-3′DsiRNAmm Antisense Strand: 3′-XXXXXXXXEXXXXXXXXXXXXXXXXXX-5′Target RNA Sequence:5′...XXXXXXXAXXXXXXXXXXX...-3′DsiRNAmm Sense Strand: 5′-XXXXXXXBXXXXXXXXXXXXXXXDD-3′DsiRNAmm Antisense Strand: -XXXXXXXXXEXXXXXXXXXXXXXXXXX-5′Target RNA Sequence:5′-...XXXXXXXXAXXXXXXXXXX...-3′DsiRNAmm Sense Strand: 5′-XXXXXXXXBXXXXXXXXXXXXXXDD-3′DsiRNAmm Antisense Strand: -XXXXXXXXXXEXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “D”=DNA and “E”=Nucleic acid residues (RNA, DNA ornon-natural or modified nucleic acids) that do not base pair (hydrogenbond) with corresponding “A” RNA residues of otherwise complementary(target) strand when strands are annealed, yet optionally do base pairwith corresponding “B” residues (“B” residues are also RNA, DNA ornon-natural or modified nucleic acids). Any of the residues of suchagents can optionally be 2′-O-methyl RNA monomers—alternatingpositioning of 2′-O-methyl RNA monomers that commences from the3′-terminal residue of the bottom (second) strand, as shown above, canalso be used in the above DsiRNA agents.

In certain embodiments, the guide strand of a dsRNA of the inventionthat is sufficiently complementary to a target RNA (e.g., mRNA) along atleast 19 nucleotides of the target gene sequence to reduce target geneexpression is not perfectly complementary to the at least 19 nucleotidelong target gene sequence. Rather, it is appreciated that the guidestrand of a dsRNA of the invention that is sufficiently complementary toa target mRNA along at least 19 nucleotides of a target RNA sequence toreduce target gene expression can have one, two, three, or even four ormore nucleotides that are mismatched with the 19 nucleotide or longertarget strand sequence. Thus, for a 19 nucleotide target RNA sequence,the guide strand of a dsRNA of the invention can be sufficientlycomplementary to the target RNA sequence to reduce target gene levelswhile possessing, e.g., only 15/19, 16/19, 17/19 or 18/19 matchednucleotide residues between guide strand and target RNA sequence.

In addition to the above-exemplified structures, dsRNAs of the inventioncan also possess one, two or three additional residues that form furthermismatches with the target α-1 antitrypsin RNA sequence. Such mismatchescan be consecutive, or can be interspersed by nucleotides that formmatched base pairs with the target α-1 antitrypsin RNA sequence. Whereinterspersed by nucleotides that form matched base pairs, mismatchedresidues can be spaced apart from each other within a single strand atan interval of one, two, three, four, five, six, seven or even eightbase paired nucleotides between such mismatch-forming residues.

As for the above-described DsiRNAmm agents, a preferred location withindsRNAs (e.g., DsiRNAs) for antisense strand nucleotides that formmismatched base pairs with target α-1 antitrypsin RNA sequence (yet mayor may not form mismatches with corresponding sense strand nucleotides)is within the antisense strand region that is located 3′ (downstream) ofthe antisense strand sequence which is complementary to the projectedAgo2 cut site of the DsiRNA (e.g., in FIG. 1 , the region of theantisense strand which is 3′ of the projected Ago2 cut site is preferredfor mismatch-forming residues and happens to be located at positions17-23 of the antisense strand for the 25/27mer agent shown in FIG. 1 ).Thus, in one embodiment, the position of a mismatch nucleotide (inrelation to the target α-1 antitrypsin RNA sequence) of the antisensestrand of a DsiRNAmm is the nucleotide residue of the antisense strandthat is located immediately 3′ (downstream) within the antisense strandsequence of the projected Ago2 cleavage site of the corresponding targetα-1 antitrypsin RNA sequence. In other preferred embodiments, a mismatchnucleotide of the antisense strand of a DsiRNAmm (in relation to thetarget α-1 antitrypsin RNA sequence) is positioned at the nucleotideresidue of the antisense strand that is located two nucleotides 3′(downstream) of the corresponding projected Ago2 cleavage site, threenucleotides 3′ (downstream) of the corresponding projected Ago2 cleavagesite, four nucleotides 3′ (downstream) of the corresponding projectedAgo2 cleavage site, five nucleotides 3′ (downstream) of thecorresponding projected Ago2 cleavage site, six nucleotides 3′(downstream) of the projected Ago2 cleavage site, seven nucleotides 3′(downstream) of the projected Ago2 cleavage site, eight nucleotides 3′(downstream) of the projected Ago2 cleavage site, or nine nucleotides 3′(downstream) of the projected Ago2 cleavage site.

In dsRNA agents possessing two mismatch-forming nucleotides of theantisense strand (where mismatch-forming nucleotides are mismatchforming in relation to target α-1 antitrypsin RNA sequence), mismatchescan occur consecutively (e.g., at consecutive positions along theantisense strand nucleotide sequence). Alternatively, nucleotides of theantisense strand that form mismatched base pairs with the target α-1antitrypsin RNA sequence can be interspersed by nucleotides that basepair with the target α-1 antitrypsin RNA sequence (e.g., for a DsiRNApossessing mismatch-forming nucleotides at positions 17 and 20 (startingfrom the 5′ terminus (position 1) of the antisense strand of the25/27mer agent shown in FIG. 1 ), but not at positions 18 and 19, themismatched residues of sense strand positions 17 and 20 are interspersedby two nucleotides that form matched base pairs with correspondingresidues of the target α-1 antitrypsin RNA sequence). For example, tworesidues of the antisense strand (located within the mismatch-tolerantregion of the antisense strand) that form mismatched base pairs with thecorresponding target α-1 antitrypsin RNA sequence can occur with zero,one, two, three, four or five matched base pairs (with respect to targetα-1 antitrypsin RNA sequence) located between these mismatch-formingbase pairs.

For certain dsRNAs possessing three mismatch-forming base pairs(mismatch-forming with respect to target α-1 antitrypsin RNA sequence),mismatch-forming nucleotides can occur consecutively (e.g., in a tripletalong the antisense strand nucleotide sequence). Alternatively,nucleotides of the antisense strand that form mismatched base pairs withthe target α-1 antitrypsin RNA sequence can be interspersed bynucleotides that form matched base pairs with the target α-1 antitrypsinRNA sequence (e.g., for a DsiRNA possessing mismatched nucleotides atpositions 17, 18 and 22, but not at positions 19, 20 and 21, themismatch-forming residues of antisense strand positions 17 and 18 areadjacent to one another, while the mismatch-forming residues ofantisense strand positions 18 and 22 are interspersed by threenucleotides that form matched base pairs with corresponding residues ofthe target α-1 antitrypsin RNA). For example, three residues of theantisense strand (located within the mismatch-tolerant region of theantisense strand) that form mismatched base pairs with the correspondingtarget α-1 antitrypsin RNA sequence can occur with zero, one, two, threeor four matched base pairs located between any two of thesemismatch-forming base pairs.

For certain dsRNAs possessing four mismatch-forming base pairs(mismatch-forming with respect to target α-1 antitrypsin RNA sequence),mismatch-forming nucleotides can occur consecutively (e.g., in aquadruplet along the sense strand nucleotide sequence). Alternatively,nucleotides of the antisense strand that form mismatched base pairs withthe target α-1 antitrypsin RNA sequence can be interspersed bynucleotides that form matched base pairs with the target α-1 antitrypsinRNA sequence (e.g., for a DsiRNA possessing mismatch-forming nucleotidesat positions 17, 19, 21 and 22, but not at positions 18 and 20, themismatch-forming residues of antisense strand positions 21 and 22 areadjacent to one another, while the mismatch-forming residues ofantisense strand positions 17 and 19 are interspersed by one nucleotidethat forms a matched base pair with the corresponding residue of thetarget α-1 antitrypsin RNA sequence—similarly, the mismatch-formingresidues of antisense strand positions 19 and 21 are also interspersedby one nucleotide that forms a matched base pair with the correspondingresidue of the target α-1 antitrypsin RNA sequence). For example, fourresidues of the antisense strand (located within the mismatch-tolerantregion of the antisense strand) that form mismatched base pairs with thecorresponding target α-1 antitrypsin RNA sequence can occur with zero,one, two or three matched base pairs located between any two of thesemismatch-forming base pairs.

The above DsiRNAmm and other dsRNA structures are described in order toexemplify certain structures of DsiRNAmm and dsRNA agents. Design of theabove DsiRNAmm and dsRNA structures can be adapted to generate, e.g.,DsiRNAmm forms of other DsiRNA structures shown infra. As exemplifiedabove, dsRNAs can also be designed that possess single mismatches (ortwo, three or four mismatches) between the antisense strand of the dsRNAand a target sequence, yet optionally can retain perfect complementaritybetween sense and antisense strand sequences of a dsRNA.

It is further noted that the dsRNA agents exemplified infra can alsopossess insertion/deletion (in/del) structures within theirdouble-stranded and/or target α-1 antitrypsin RNA-aligned structures.Accordingly, the dsRNAs of the invention can be designed to possessin/del variations in, e.g., antisense strand sequence as compared totarget α-1 antitrypsin RNA sequence and/or antisense strand sequence ascompared to sense strand sequence, with preferred location(s) forplacement of such in/del nucleotides corresponding to those locationsdescribed above for positioning of mismatched and/or mismatch-formingbase pairs.

It is also noted that the DsiRNAs of the instant invention can toleratemismatches within the 3′-terminal region of the sense strand/5′-terminalregion of the antisense strand, as this region is modeled to beprocessed by Dicer and liberated from the guide strand sequence thatloads into RISC. Exemplary DsiRNA structures of the invention thatharbor such mismatches include the following:

Target RNA Sequence: 5′-...XXXXXXXXXXXXXXXXXXXXXHXXX...-3′DsiRNA Sense Strand: 5′-XXXXXXXXXXXXXXXXXXXXXIXDD-3′DsiRNA Antisense Strand: 3′-XXXXXXXXXXXXXXXXXXXXXXXJXXX-5′Target RNA Sequence: 5′-...XXXXXXXXXXXXXXXXXXXXXXHXX...-3′DsiRNA Sense Strand: 5′-XXXXXXXXXXXXXXXXXXXXXXIDD-3′DsiRNA Antisense Strand: 3′-XXXXXXXXXXXXXXXXXXXXXXXXJXX-5′Target RNA Sequence: 5′-...XXXXXXXXXXXXXXXXXXXXXXXHX...-3′DsiRNA Sense Strand: 5′-XXXXXXXXXXXXXXXXXXXXXXXID-3′DsiRNA Antisense Strand: 3′-XXXXXXXXXXXXXXXXXXXXXXXXXJX-5′Target RNA Sequence: 5′-...XXXXXXXXXXXXXXXXXXXXXXXXH...-3′DsiRNA Sense Strand: 5′-XXXXXXXXXXXXXXXXXXXXXXXDI-3′DsiRNA Antisense Strand: 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXJ-5′wherein “X”=RNA, “D”=DNA and “I” and “J”=Nucleic acid residues (RNA, DNAor non-natural or modified nucleic acids) that do not base pair(hydrogen bond) with one another, yet optionally “J” is complementary totarget RNA sequence nucleotide “H”. Any of the residues of such agentscan optionally be 2′-O-methyl RNA monomers—alternating positioning of2′-O-methyl RNA monomers that commences from the 3′-terminal residue ofthe bottom (second) strand, as shown above—or any of the above-describedmethylation patterns—can also be used in the above DsiRNA agents. Theabove mismatches can also be combined within the DsiRNAs of the instantinvention.

In the below exemplary structures, such mismatches are introduced withinthe asymmetric AAT-506 DsiRNA (newly-introduced mismatch residues areitalicized):

AAT-506 25/27mer DsiRNA, mismatch position=19 of sense strand (from5′-terminus)

(SEQ ID NO: 3326) 5′-UCUUCUUCUCCCCAGUGA^(A)CAUCgc-3′ (SEQ ID NO: 213)3′-AUAGAAGAAGAGGGGUCA_(C)UCGUAGCG-5′ Optionally, the mismatched ‘A’ residue of position 19 of the sensestrand is alternatively ‘U’ or ‘C’.AAT-506 25/27mer DsiRNA, mismatch position=20 of sense strand (from5′-terminus)

(SEQ ID NO: 3327) 5′-UCUUCUUCUCCCCAGUGAG^(U)AUCgc-3′ (SEQ ID NO: 213)3′-AUAGAAGAAGAGGGGUCACUC_(G)UAGCG-5′Optionally, the mismatched ‘U’ residue of position 20 of the sensestrand is alternatively ‘A’ or ‘G’.AAT-506 25/27mer DsiRNA, mismatch position=21 of sense strand (from5′-terminus)

(SEQ ID NO: 3328) 5′-UCUUCUUCUCCCCAGUGAGC^(U)UCgc-3′ (SEQ ID NO: 213)3′-AUAGAAGAAGAGGGGUCACUCG_(U)AGCG-5′Optionally, the mismatched ‘U’ residue of position 21 of the sensestrand is alternatively ‘G’ or ‘C’.AAT-506 25/27mer DsiRNA, mismatch position=22 of sense strand (from5′-terminus)

(SEQ ID NO: 3329) 5′-UCUUCUUCUCCCCAGUGAGCA^(G)Cgc-3′ (SEQ ID NO: 213)3′-AUAGAAGAAGAGGGGUCACUCGU_(A)GCG-5′Optionally, the mismatched ‘G’ residue of position 22 of the sensestrand is alternatively ‘A’ or ‘C’.AAT-506 25/27mer DsiRNA, mismatch position=23 of sense strand (from5′-terminus)

(SEQ ID NO: 3330) 5′-UCUUCUUCUCCCCAGUGAGCAU^(A)gc-3′ (SEQ ID NO: 213)3′-AUAGAAGAAGAGGGGUCACUCGUA_(G)CG-5′Optionally, the mismatched ‘A’ residue of position 23 of the sensestrand is alternatively ‘U’ or ‘G’.AAT-506 25/27mer DsiRNA, mismatch position=24 of sense strand (from5′-terminus)

(SEQ ID NO: 3331) 5′-UCUUCUUCUCCCCAGUGAGCAUC^(t)c-3′ (SEQ ID NO: 213)3′-AUAGAAGAAGAGGGGUCACUCGUAG_(C)G-5′Optionally, the mismatched ‘t’ residue of position 24 of the sensestrand is alternatively ‘a’ or ‘c’.AAT-506 25/27mer DsiRNA, mismatch position=25 of sense strand (from5′-terminus)

(SEQ ID NO: 3332) 5′-UCUUCUUCUCCCCAGUGAGCAUCg^(a)-3′ (SEQ ID NO: 213)3′-AUAGAAGAAGAGGGGUCACUCGUAGC_(G)-5′Optionally, the mismatched ‘a’ residue of position 25 of the sensestrand is alternatively ‘t’ or ‘g’.AAT-506 25/27mer DsiRNA, mismatch position=1 of antisense strand (from5′-terminus)

(SEQ ID NO: 15) 5′-UCUUCUUCUCCCCAGUGAGCAUCg^(c)-3′ (SEQ ID NO: 3333)3′-AUAGAAGAAGAGGGGUCACUCGUAGC_(U)-5′Optionally, the mismatched ‘U’ residue of position 1 of the antisensestrand is alternatively ‘A’ or ‘C’.AAT-506 25/27mer DsiRNA, mismatch position=2 of antisense strand (from5′-terminus)

(SEQ ID NO: 15) 5′-UCUUCUUCUCCCCAGUGAGCAUC^(g)c-3′ (SEQ ID NO: 3334)3′-AUAGAAGAAGAGGGGUCACUCGUAG_(A)G-5′Optionally, the mismatched ‘A’ residue of position 2 of the antisensestrand is alternatively ‘U’ or ‘G’.AAT-506 25/27mer DsiRNA, mismatch position=3 of antisense strand (from5′-terminus)

(SEQ ID NO: 15) 5′-UCUUCUUCUCCCCAGUGAGCAU^(C)gc-3′ (SEQ ID NO: 3335)3′-AUAGAAGAAGAGGGGUCACUCGUA_(U)CG-5′Optionally, the mismatched ‘U’ residue of position 3 of the antisensestrand is alternatively ‘A’ or ‘C’.AAT-506 25/27mer DsiRNA, mismatch position=4 of antisense strand (from5′-terminus)

(SEQ ID NO: 15) 5′-UCUUCUUCUCCCCAGUGAGCA^(U)Cgc-3′ (SEQ ID NO: 3336)3′-AUAGAAGAAGAGGGGUCACUCGU_(C)GCG-5′Optionally, the mismatched ‘C’ residue of position 4 of the antisensestrand is alternatively ‘U’ or ‘G’.AAT-506 25/27mer DsiRNA, mismatch position=5 of antisense strand (from5′-terminus)

(SEQ ID NO: 15) 5′-UCUUCUUCUCCCCAGUGAGC^(A)UCgc-3′ (SEQ ID NO: 3337)3′-AUAGAAGAAGAGGGGUCACUCG_(A)AGCG-5′Optionally, the mismatched ‘A’ residue of position 5 of the antisensestrand is alternatively ‘C’ or ‘G’.AAT-506 25/27mer DsiRNA, mismatch position=6 of antisense strand (from5′-terminus)

(SEQ ID NO: 15) 5′-UCUUCUUCUCCCCAGUGAG^(C)AUCgc-3′ (SEQ ID NO: 3338)3′-AUAGAAGAAGAGGGGUCACUC_(A)UAGCG-5′Optionally, the mismatched ‘A’ residue of position 6 of the antisensestrand is alternatively ‘U’ or ‘C’.AAT-506 25/27mer DsiRNA, mismatch position=7 of antisense strand (from5′-terminus)

(SEQ ID NO: 15) 5′-UCUUCUUCUCCCCAGUGA^(G)CAUCgc-3′ (SEQ ID NO: 3339)3′-AUAGAAGAAGAGGGGUCACU_(U)GUAGCG-5′Optionally, the mismatched ‘U’ residue of position 7 of the antisensestrand is alternatively ‘A’ or ‘G’.

As another example, in the below structures, such mismatches areintroduced within the asymmetric AAT-1059 DsiRNA (newly-introducedmismatch residues are italicized):

AAT-1059 25/27mer DsiRNA, mismatch position=19 of sense strand (from5′-terminus)

(SEQ ID NO: 3340) 5′-GCUGUCCAGCUGGGUGCU^(A)CUGAtg-3′ (SEQ ID NO: 285)3′-UUCGACAGGUCGACCCACGA_(C)GACUAC-5′Optionally, the mismatched ‘A’ residue of position 19 of the sensestrand is alternatively ‘U’ or ‘C’.AAT-1059 25/27mer DsiRNA, mismatch position=20 of sense strand (from5′-terminus)

(SEQ ID NO: 3341) 5′-GCUGUCCAGCUGGGUGCUG^(U)UGAtg-3′ (SEQ ID NO: 285)3′-UUCGACAGGUCGACCCACGAC_(G)ACUAC-5′Optionally, the mismatched ‘U’ residue of position 20 of the sensestrand is alternatively ‘A’ or ‘G’.AAT-1059 25/27mer DsiRNA, mismatch position=21 of sense strand (from5′-terminus)

(SEQ ID NO: 3342) 5′-GCUGUCCAGCUGGGUGCUGC^(A)GAtg-3′ (SEQ ID NO: 285)3′-UUCGACAGGUCGACCCACGACG_(A)CUAC-5′Optionally, the mismatched ‘A’ residue of position 21 of the sensestrand is alternatively ‘C’ or ‘G’.AAT-1059 25/27mer DsiRNA, mismatch position=22 of sense strand (from5′-terminus)

(SEQ ID NO: 3343) 5′-GCUGUCCAGCUGGGUGCUGCU^(U)Atg-3′ (SEQ ID NO: 285)3′-UUCGACAGGUCGACCCACGACGA_(C)UAC-5′Optionally, the mismatched ‘U’ residue of position 22 of the sensestrand is alternatively ‘A’ or ‘C’.AAT-1059 25/27mer DsiRNA, mismatch position=23 of sense strand (from5′-terminus)

(SEQ ID NO: 3344) 5′-GCUGUCCAGCUGGGUGCUGCUG^(U)tg-3′ (SEQ ID NO: 285)3′-UUCGACAGGUCGACCCACGACGAC_(U)AC-5′Optionally, the mismatched ‘U’ residue of position 23 of the sensestrand is alternatively ‘C’ or ‘G’.AAT-1059 25/27mer DsiRNA, mismatch position=24 of sense strand (from5′-terminus)

(SEQ ID NO: 3345) 5′-GCUGUCCAGCUGGGUGCUGCUGA^(g)g-3′ (SEQ ID NO: 285)3′-UUCGACAGGUCGACCCACGACGACU_(A)C-5′Optionally, the mismatched ‘g’ residue of position 24 of the sensestrand is alternatively ‘a’ or ‘c’.AAT-1059 25/27mer DsiRNA, mismatch position=25 of sense strand (from5′-terminus)

(SEQ ID NO: 3346) 5′-GCUGUCCAGCUGGGUGCUGCUGAt^(a)-3′ (SEQ ID NO: 285)3′-UUCGACAGGUCGACCCACGACGACUA_(C)-5′Optionally, the mismatched ‘a’ residue of position 25 of the sensestrand is alternatively ‘t’ or ‘c’.AAT-1059 25/27mer DsiRNA, mismatch position=1 of antisense strand (from5′-terminus)

(SEQ ID NO: 87) 5′-GCUGUCCAGCUGGGUGCUGCUGAt^(g)-3′ (SEQ ID NO: 3347)3′-UUCGACAGGUCGACCCACGACGACUA_(U)-5′Optionally, the mismatched ‘U’ residue of position 1 of the antisensestrand is alternatively ‘A’ or ‘G’.AAT-1059 25/27mer DsiRNA, mismatch position=2 of antisense strand (from5′-terminus)

(SEQ ID NO: 87) 5′-GCUGUCCAGCUGGGUGCUGCUGA^(t)g-3′ (SEQ ID NO: 3348)3′-UUCGACAGGUCGACCCACGACGACU_(C)C-5′Optionally, the mismatched ‘C’ residue of position 2 of the antisensestrand is alternatively ‘U’ or ‘G’.AAT-1059 25/27mer DsiRNA, mismatch position=3 of antisense strand (from5′-terminus)

(SEQ ID NO: 87) 5′-GCUGUCCAGCUGGGUGCUGCUG^(A)tg-3′ (SEQ ID NO: 3349)3′-UUCGACAGGUCGACCCACGACGAC_(A)AC-5′Optionally, the mismatched ‘A’ residue of position 3 of the antisensestrand is alternatively ‘C’ or ‘G’.AAT-1059 25/27mer DsiRNA, mismatch position=4 of antisense strand (from5′-terminus)

(SEQ ID NO: 87) 5′-GCUGUCCAGCUGGGUGCUGCU^(G)Atg-3′ (SEQ ID NO: 3350)3′-UUCGACAGGUCGACCCACGACGA_(A)UAC-5′Optionally, the mismatched ‘A’ residue of position 4 of the antisensestrand is alternatively ‘U’ or ‘G’.AAT-1059 25/27mer DsiRNA, mismatch position=5 of antisense strand (from5′-terminus)

(SEQ ID NO: 87) 5′-GCUGUCCAGCUGGGUGCUGC^(U)GAtg-3′ (SEQ ID NO: 3351)3′-UUCGACAGGUCGACCCACGACG_(U)CUAC-5′Optionally, the mismatched ‘U’ residue of position 5 of the antisensestrand is alternatively ‘C’ or ‘G’.AAT-1059 25/27mer DsiRNA, mismatch position=6 of antisense strand (from5′-terminus)

(SEQ ID NO: 87) 5′-GCUGUCCAGCUGGGUGCUG^(C)UGAtg-3′ (SEQ ID NO: 3352)3′-UUCGACAGGUCGACCCACGAC_(A)ACUAC-5′Optionally, the mismatched ‘A’ residue of position 6 of the antisensestrand is alternatively ‘U’ or ‘C’.AAT-1059 25/27mer DsiRNA, mismatch position=7 of antisense strand (from5′-terminus)

(SEQ ID NO: 87) 5′-GCUGUCCAGCUGGGUGCU^(G)CUGAtg-3′ (SEQ ID NO: 3353)3′-UUCGACAGGUCGACCCACGA_(U)GACUAC-5′Optionally, the mismatched ‘U’ residue of position 7 of the antisensestrand is alternatively ‘A’ or ‘G’.

For the above oligonucleotide strand sequences, it is contemplated thatthe sense strand sequence of one depicted duplex can be combined with anantisense strand of another depicted duplex, thereby forming a distinctduplex—in certain instances, such duplexes contain a mismatched residuewith respect to the α-1 antitrypsin target transcript sequence, whilesuch sense and antisense strand sequences do not present a mismatch atthis residue with respect to one another (e.g., duplexes comprising SEQID NOs: 3326 and 3339; SEQ ID NOs: 3327 and 3338; SEQ ID NOs: 3328 and3337, etc., are contemplated as exemplary of such duplexes).

As noted above, introduction of mismatches can be performed upon any ofthe DsiRNAs described herein.

The mismatches of such DsiRNA structures can be combined to produce aDsiRNA possessing, e.g., two, three or even four mismatches within the3′-terminal four to seven nucleotides of the sense strand/5′-terminalfour to seven nucleotides of the antisense strand.

Indeed, in view of the flexibility of sequences which can beincorporated into DsiRNAs at the 3′-terminal residues of the sensestrand/5′-terminal residues of the antisense strand, in certainembodiments, the sequence requirements of an asymmetric DsiRNA of theinstant invention can be represented as the following (minimalist)structure (shown for an exemplary α-1 antitrypsin-506 DsiRNA sequence):

(SEQ ID NO: 3354) 5′-UCUUCUUCUCCCCAGUGAXXXXXX[X]_(n)-3′(SEQ ID NO: 3355) 3′-AUAGAAGAAGAGGGGUCACUXXXXXX[X]_(n)-5′where n=1 to 5, 1 to 10, 1 to 20, 1 to 30, 1 to 50, or 1 to 80 or more.

α-1 antitrypsin-506 mRNA Target: (SEQ ID NO: 3356)5′-UAUCUUCUUCUCCCCAGUGAXXXXXXX-3′.

The α-1 antitrypsin target site may also be a site which is targeted byone or more of several oligonucleotides whose complementary target sitesoverlap with a stated target site. For example, for an exemplary α-1antitrypsin-506 DsiRNA, it is noted that certain DsiRNAs targetingoverlapping and only slightly offset α-1 antitrypsin sequences couldexhibit activity levels similar to that of α-1 antitrypsin-506 (e.g.,α-1 antitrypsin-500 to 513 of Table 2 above). Thus, in certainembodiments, a designated target sequence region might be effectivelytargeted by a series of DsiRNAs possessing largely overlappingsequences. (E.g., if considering DsiRNAs of the α-1 antitrypsin-500 toα-1 antitrypsin-513 target site(s), a more encompassing α-1 antitrypsintranscript target sequence might be recited as, e.g.,5′-CACCAAUAUCUUCUUCUCCCCAGUGAGCAUCGCU-3′ (SEQ ID NO: 3357), wherein anygiven DsiRNA (e.g., a DsiRNA selected from α-1 antitrypsin-500 to α-1antitrypsin-513) only targets a sub-sequence within such a sequenceregion, yet the entire sequence can be considered a viable target forsuch a series of DsiRNAs).

Additionally and/or alternatively, mismatches within the 3′-terminalseven nucleotides of the sense strand/5′-terminal seven nucleotides ofthe antisense strand can be combined with mismatches positioned at othermismatch-tolerant positions, as described above.

In view of the present identification of the above-described Dicersubstrate agents (DsiRNAs) as inhibitors of α-1 antitrypsin levels viatargeting of specific α-1 antitrypsin sequences, it is also recognizedthat dsRNAs having structures similar to those described herein can alsobe synthesized which target other sequences within the α-1 antitrypsinsequence of NM_000295.4, or within variants thereof (e.g., targetsequences possessing 80% identity, 90% identity, 95% identity, 96%identity, 97% identity, 98% identity, 99% or more identity to a sequenceof NM_000295.4).

Anti-α-1 Antitrypsin DsiRNA Design/Synthesis

It has been found empirically that longer dsRNA species of from 25 to 35nucleotides (DsiRNAs) and especially from 25 to 30 nucleotides giveunexpectedly effective results in terms of potency and duration ofaction, as compared to 19-23mer siRNA agents. Without wishing to bebound by the underlying theory of the dsRNA processing mechanism, it isthought that the longer dsRNA species serve as a substrate for the Dicerenzyme in the cytoplasm of a cell. In addition to cleaving the dsRNA ofthe invention into shorter segments, Dicer is thought to facilitate theincorporation of a single-stranded cleavage product derived from thecleaved dsRNA into the RISC complex that is responsible for thedestruction of the cytoplasmic RNA (e.g., α-1 antitrypsin RNA) of orderived from the target gene, α-1 antitrypsin (or other gene associatedwith a α-1 antitrypsin-associated disease or disorder). Prior studies(Rossi et al., U.S. Patent Application No. 2007/0265220) have shown thatthe cleavability of a dsRNA species (specifically, a DsiRNA agent) byDicer corresponds with increased potency and duration of action of thedsRNA species.

Certain preferred anti-α-1 antitrypsin DsiRNA agents were selected froma pre-screened population. Design of DsiRNAs can optionally involve useof predictive scoring algorithms that perform in silico assessments ofthe projected activity/efficacy of a number of possible DsiRNA agentsspanning a region of sequence. Information regarding the design of suchscoring algorithms can be found, e.g., in Gong et al. (BMCBioinformatics 2006, 7:516), though a more recent “v4.3” algorithmrepresents a theoretically improved algorithm relative to siRNA scoringalgorithms previously available in the art. (E.g., “v3” and “v4” scoringalgorithms are machine learning algorithms that are not reliant upon anybiases in human sequence. In addition, the “v3” and “v4” algorithmsderive from data sets that are many-fold larger than that from which anolder “v2” algorithm such as that described in Gong et al. derives.)

The first and second oligonucleotides of the DsiRNA agents of theinstant invention are not required to be completely complementary. Infact, in one embodiment, the 3′-terminus of the sense strand containsone or more mismatches. In one aspect, two mismatches are incorporatedat the 3′ terminus of the sense strand. In another embodiment, theDsiRNA of the invention is a double stranded RNA molecule containing twoRNA oligonucleotides each of which is 27 nucleotides in length and, whenannealed to each other, have blunt ends and a two nucleotide mismatch onthe 3′-terminus of the sense strand (the 5′-terminus of the antisensestrand). The use of mismatches or decreased thermodynamic stability(specifically at the 3′-sense/5′-antisense position) has been proposedto facilitate or favor entry of the antisense strand into RISC (Schwarzet al., 2003, Cell 115: 199-208; Khvorova et al., 2003, Cell 115:209-216), presumably by affecting some rate-limiting unwinding stepsthat occur with entry of the siRNA into RISC. Thus, terminal basecomposition has been included in design algorithms for selecting active21mer siRNA duplexes (Ui-Tei et al., 2004, Nucleic Acids Res 32:936-948; Reynolds et al., 2004, Nat Biotechnol 22: 326-330). With Dicercleavage of the dsRNA of this embodiment, the small end-terminalsequence which contains the mismatches will either be left unpaired withthe antisense strand (become part of a 3′-overhang) or be cleavedentirely off the final 21-mer siRNA. These “mismatches”, therefore, donot persist as mismatches in the final RNA component of RISC. Thefinding that base mismatches or destabilization of segments at the3′-end of the sense strand of Dicer substrate improved the potency ofsynthetic duplexes in RNAi, presumably by facilitating processing byDicer, was a surprising finding of past works describing the design anduse of 25-30mer dsRNAs (also termed “DsiRNAs” herein; Rossi et al., U.S.Patent Application Nos. 2005/0277610, 2005/0244858 and 2007/0265220).

Modification of Anti-α-1 Antitrypsin dsRNAs

One major factor that inhibits the effect of double stranded RNAs(“dsRNAs”) is the degradation of dsRNAs (e.g., siRNAs and DsiRNAs) bynucleases. A 3′-exonuclease is the primary nuclease activity present inserum and modification of the 3′-ends of antisense DNA oligonucleotidesis crucial to prevent degradation (Eder et al., 1991, Antisense Res Dev,1: 141-151). An RNase-T family nuclease has been identified called ERI-1which has 3′ to 5′ exonuclease activity that is involved in regulationand degradation of siRNAs (Kennedy et al., 2004, Nature 427: 645-649;Hong et al., 2005, Biochem J, 390: 675-679). This gene is also known asThex1 (NM_02067) in mice or THEX1 (NM_153332) in humans and is involvedin degradation of histone mRNA; it also mediates degradation of3′-overhangs in siRNAs, but does not degrade duplex RNA (Yang et al.,2006, J Biol Chem, 281: 30447-30454). It is therefore reasonable toexpect that 3′-end-stabilization of dsRNAs, including the DsiRNAs of theinstant invention, will improve stability.

XRN1 (NM_019001) is a 5′ to 3′ exonuclease that resides in P-bodies andhas been implicated in degradation of mRNA targeted by miRNA (Rehwinkelet al., 2005, RNA 11: 1640-1647) and may also be responsible forcompleting degradation initiated by internal cleavage as directed by asiRNA. XRN2 (NM_012255) is a distinct 5′ to 3′ exonuclease that isinvolved in nuclear RNA processing.

RNase A is a major endonuclease activity in mammals that degrades RNAs.It is specific for ssRNA and cleaves at the 3′-end of pyrimidine bases.SiRNA degradation products consistent with RNase A cleavage can bedetected by mass spectrometry after incubation in serum (Turner et al.,2007, Mol Biosyst 3: 43-50). The 3′-overhangs enhance the susceptibilityof siRNAs to RNase degradation. Depletion of RNase A from serum reducesdegradation of siRNAs; this degradation does show some sequencepreference and is worse for sequences having poly A/U sequence on theends (Haupenthal et al., 2006 Biochem Pharmacol 71: 702-710). Thissuggests the possibility that lower stability regions of the duplex may“breathe” and offer transient single-stranded species available fordegradation by RNase A. RNase A inhibitors can be added to serum andimprove siRNA longevity and potency (Haupenthal et al., 2007, Int J.Cancer 121: 206-210).

In 21mers, phosphorothioate or boranophosphate modifications directlystabilize the internucleoside phosphate linkage. Boranophosphatemodified RNAs are highly nuclease resistant, potent as silencing agents,and are relatively non-toxic. Boranophosphate modified RNAs cannot bemanufactured using standard chemical synthesis methods and instead aremade by in vitro transcription (IVT) (Hall et al., 2004, Nucleic AcidsRes 32: 5991-6000; Hall et al., 2006, Nucleic Acids Res 34: 2773-2781).Phosphorothioate (PS) modifications can be easily placed in the RNAduplex at any desired position and can be made using standard chemicalsynthesis methods. The PS modification shows dose-dependent toxicity, somost investigators have recommended limited incorporation in siRNAs,favoring the 3′-ends where protection from nucleases is most important(Harborth et al., 2003, Antisense Nucleic Acid Drug Dev 13: 83-105; Chiuand Rana, 2003, Mol Cell 10: 549-561; Braasch et al., 2003, Biochemistry42: 7967-7975; Amarzguioui et al., 2003, Nucleic Acids Research 31:589-595). More extensive PS modification can be compatible with potentRNAi activity; however, use of sugar modifications (such as 2′-O-methylRNA) may be superior (Choung et al., 2006, Biochem Biophys Res Commun342: 919-927).

A variety of substitutions can be placed at the 2′-position of theribose which generally increases duplex stability (T_(m)) and cangreatly improve nuclease resistance. 2′-O-methyl RNA is a naturallyoccurring modification found in mammalian ribosomal RNAs and transferRNAs. 2′-O-methyl modification in siRNAs is known, but the preciseposition of modified bases within the duplex is important to retainpotency and complete substitution of 2′-O-methyl RNA for RNA willinactivate the siRNA. For example, a pattern that employs alternating2′-O-methyl bases can have potency equivalent to unmodified RNA and isquite stable in serum (Choung et al., 2006, Biochem Biophys Res Commun342: 919-927; Czauderna et al., 2003, Nucleic Acids Research 31:2705-2716).

The 2′-fluoro (2′-F) modification is also compatible with dsRNA (e.g.,siRNA and DsiRNA) function; it is most commonly placed at pyrimidinesites (due to reagent cost and availability) and can be combined with2′-O-methyl modification at purine positions; 2′-F purines are availableand can also be used. Heavily modified duplexes of this kind can bepotent triggers of RNAi in vitro (Allerson et al., 2005, J Med Chem 48:901-904; Prakash et al., 2005, J Med Chem 48: 4247-4253; Kraynack andBaker, 2006, RNA 12: 163-176) and can improve performance and extendduration of action when used in vivo (Morrissey et al., 2005, Hepatology41: 1349-1356; Morrissey et al., 2005, Nat Biotechnol 23: 1002-1007). Ahighly potent, nuclease stable, blunt 19mer duplex containingalternative 2′-F and 2′-O-Me bases is taught by Allerson. In thisdesign, alternating 2′-O-Me residues are positioned in an identicalpattern to that employed by Czauderna, however the remaining RNAresidues are converted to 2′-F modified bases. A highly potent, nucleaseresistant siRNA employed by Morrissey employed a highly potent, nucleaseresistant siRNA in vivo. In addition to 2′-O-Me RNA and 2′-F RNA, thisduplex includes DNA, RNA, inverted abasic residues, and a 3′-terminal PSinternucleoside linkage. While extensive modification has certainbenefits, more limited modification of the duplex can also improve invivo performance and is both simpler and less costly to manufacture.Soutschek et al. (2004, Nature 432: 173-178) employed a duplex in vivoand was mostly RNA with two 2′-O-Me RNA bases and limited 3′-terminal PSinternucleoside linkages.

Locked nucleic acids (LNAs) are a different class of 2′-modificationthat can be used to stabilize dsRNA (e.g., siRNA and DsiRNA). Patternsof LNA incorporation that retain potency are more restricted than2′-O-methyl or 2′-F bases, so limited modification is preferred (Braaschet al., 2003, Biochemistry 42: 7967-7975; Grunweller et al., 2003,Nucleic Acids Res 31: 3185-3193; Elmen et al., 2005, Nucleic Acids Res33: 439-447). Even with limited incorporation, the use of LNAmodifications can improve dsRNA performance in vivo and may also alteror improve off target effect profiles (Mook et al., 2007, Mol CancerTher 6: 833-843).

Synthetic nucleic acids introduced into cells or live animals can berecognized as “foreign” and trigger an immune response. Immunestimulation constitutes a major class of off-target effects which candramatically change experimental results and even lead to cell death.The innate immune system includes a collection of receptor moleculesthat specifically interact with DNA and RNA that mediate theseresponses, some of which are located in the cytoplasm and some of whichreside in endosomes (Marques and Williams, 2005, Nat Biotechnol 23:1399-1405; Schlee et al., 2006, Mol Ther 14: 463-470). Delivery ofsiRNAs by cationic lipids or liposomes exposes the siRNA to bothcytoplasmic and endosomal compartments, maximizing the risk fortriggering a type 1 interferon (IFN) response both in vitro and in vivo(Morrissey et al., 2005, Nat Biotechnol 23: 1002-1007; Sioud andSorensen, 2003, Biochem Biophys Res Commun 312: 1220-1225; Sioud, 2005,J Mol Biol 348: 1079-1090; Ma et al., 2005, Biochem Biophys Res Commun330: 755-759). RNAs transcribed within the cell are less immunogenic(Robbins et al., 2006, Nat Biotechnol 24: 566-571) and synthetic RNAsthat are immunogenic when delivered using lipid-based methods can evadeimmune stimulation when introduced unto cells by mechanical means, evenin vivo (Heidel et al., 2004, Nat Biotechnol 22: 1579-1582). However,lipid based delivery methods are convenient, effective, and widely used.Some general strategy to prevent immune responses is needed, especiallyfor in vivo application where all cell types are present and the risk ofgenerating an immune response is highest. Use of chemically modifiedRNAs may solve most or even all of these problems.

In certain embodiments, modifications can be included in the anti-α-1antitrypsin dsRNA agents of the present invention so long as themodification does not prevent the dsRNA agent from possessing α-1antitrypsin inhibitory activity. In one embodiment, one or moremodifications are made that enhance Dicer processing of the DsiRNA agent(an assay for determining Dicer processing of a DsiRNA is describedelsewhere herein). In a second embodiment, one or more modifications aremade that result in more effective α-1 antitrypsin inhibition (asdescribed herein, α-1 antitrypsin inhibition/α-1 antitrypsin inhibitoryactivity of a dsRNA can be assayed via art-recognized methods fordetermining RNA levels, or for determining α-1 antitrypsin polypeptidelevels, should such levels be assessed in lieu of or in addition toassessment of, e.g., α-1 antitrypsin mRNA levels). In a thirdembodiment, one or more modifications are made that support greater α-1antitrypsin inhibitory activity (means of determining α-1 antitrypsininhibitory activity are described supra). In a fourth embodiment, one ormore modifications are made that result in greater potency of α-1antitrypsin inhibitory activity per each dsRNA agent molecule to bedelivered to the cell (potency of α-1 antitrypsin inhibitory activity isdescribed supra). Modifications can be incorporated in the 3′-terminalregion, the 5′-terminal region, in both the 3′-terminal and 5′-terminalregion or in some instances in various positions within the sequence.With the restrictions noted above in mind, numbers and combinations ofmodifications can be incorporated into the dsRNA agent. Where multiplemodifications are present, they may be the same or different.Modifications to bases, sugar moieties, the phosphate backbone, andtheir combinations are contemplated. Either 5′-terminus can bephosphorylated.

Examples of modifications contemplated for the phosphate backboneinclude phosphonates, including methylphosphonate, phosphorothioate, andphosphotriester modifications such as alkylphosphotriesters, and thelike. Examples of modifications contemplated for the sugar moietyinclude 2′-alkyl pyrimidine, such as 2′-O-methyl, 2′-fluoro, amino, anddeoxy modifications and the like (see, e.g., Amarzguioui et al., 2003,Nucleic Acids Research 31: 589-595). Examples of modificationscontemplated for the base groups include abasic sugars, 2-O-alkylmodified pyrimidines, 4-thiouracil, 5-bromouracil, 5-iodouracil, and5-(3-aminoallyl)-uracil and the like. Locked nucleic acids, or LNA's,could also be incorporated. Many other modifications are known and canbe used so long as the above criteria are satisfied. Examples ofmodifications are also disclosed in U.S. Pat. Nos. 5,684,143, 5,858,988and 6,291,438 and in U.S. published patent application No. 2004/0203145A1. Other modifications are disclosed in Herdewijn (2000, AntisenseNucleic Acid Drug Dev 10: 297-310), Eckstein (2000, Antisense NucleicAcid Drug Dev 10: 117-21), Rusckowski et al. (2000, Antisense NucleicAcid Drug Dev 10: 333-345), Stein et al. (2001, Antisense Nucleic AcidDrug Dev 11: 317-25); Vorobjev et al. (2001, Antisense Nucleic Acid DrugDev 11: 77-85).

One or more modifications contemplated can be incorporated into eitherstrand. The placement of the modifications in the dsRNA agent cangreatly affect the characteristics of the dsRNA agent, includingconferring greater potency and stability, reducing toxicity, enhanceDicer processing, and minimizing an immune response. In one embodiment,the antisense strand or the sense strand or both strands have one ormore 2′-O-methyl modified nucleotides. In another embodiment, theantisense strand contains 2′-O-methyl modified nucleotides. In anotherembodiment, the antisense stand contains a 3′ overhang that is comprisedof 2′-O-methyl modified nucleotides. The antisense strand could alsoinclude additional 2′-O-methyl modified nucleotides.

In certain embodiments, the anti-α-1 antitrypsin DsiRNA agent of theinvention has several properties which enhance its processing by Dicer.According to such embodiments, the DsiRNA agent has a length sufficientsuch that it is processed by Dicer to produce an siRNA and at least oneof the following properties: (i) the DsiRNA agent is asymmetric, e.g.,has a 3′ overhang on the sense strand and (ii) the DsiRNA agent has amodified 3′ end on the antisense strand to direct orientation of Dicerbinding and processing of the dsRNA to an active siRNA. According tothese embodiments, the longest strand in the DsiRNA agent comprises25-30 nucleotides. In one embodiment, the sense strand comprises 25-30nucleotides and the antisense strand comprises 25-28 nucleotides. Thus,the resulting dsRNA has an overhang on the 3′ end of the sense strand.The overhang is 1˜4 nucleotides, such as 2 nucleotides. The antisensestrand may also have a 5′ phosphate.

In certain embodiments, the sense strand of a DsiRNA agent is modifiedfor Dicer processing by suitable modifiers located at the 3′ end of thesense strand, i.e., the DsiRNA agent is designed to direct orientationof Dicer binding and processing. Suitable modifiers include nucleotidessuch as deoxyribonucleotides, dideoxyribonucleotides, acyclonucleotidesand the like and sterically hindered molecules, such as fluorescentmolecules and the like. Acyclonucleotides substitute a2-hydroxyethoxymethyl group for the 2′-deoxyribofuranosyl sugar normallypresent in dNMPs. Other nucleotide modifiers could include3′-deoxyadenosine (cordycepin), 3′-azido-3′-deoxythymidine (AZT),2′,3′-dideoxyinosine (ddI), 2′,3′-dideoxy-3′-thiacytidine (3TC),2′,3′-didehydro-2′,3′-dideoxythymidine (d4T) and the monophosphatenucleotides of 3′-azido-3′-deoxythymidine (AZT),2′,3′-dideoxy-3′-thiacytidine (3TC) and2′,3′-didehydro-2′,3′-dideoxythymidine (d4T). In one embodiment,deoxynucleotides are used as the modifiers. When nucleotide modifiersare utilized, 1-3 nucleotide modifiers, or 2 nucleotide modifiers aresubstituted for the ribonucleotides on the 3′ end of the sense strand.When sterically hindered molecules are utilized, they are attached tothe ribonucleotide at the 3′ end of the antisense strand. Thus, thelength of the strand does not change with the incorporation of themodifiers. In another embodiment, the invention contemplatessubstituting two DNA bases in the dsRNA to direct the orientation ofDicer processing. In a further invention, two terminal DNA bases arelocated on the 3′ end of the sense strand in place of tworibonucleotides forming a blunt end of the duplex on the 5′ end of theantisense strand and the 3′ end of the sense strand, and atwo-nucleotide RNA overhang is located on the 3′-end of the antisensestrand. This is an asymmetric composition with DNA on the blunt end andRNA bases on the overhanging end.

In certain other embodiments, the antisense strand of a DsiRNA agent ismodified for Dicer processing by suitable modifiers located at the 3′end of the antisense strand, i.e., the DsiRNA agent is designed todirect orientation of Dicer binding and processing. Suitable modifiersinclude nucleotides such as deoxyribonucleotides,dideoxyribonucleotides, acyclonucleotides and the like and stericallyhindered molecules, such as fluorescent molecules and the like.Acyclonucleotides substitute a 2-hydroxyethoxymethyl group for the2′-deoxyribofuranosyl sugar normally present in dNMPs. Other nucleotidemodifiers could include 3′-deoxyadenosine (cordycepin),3′-azido-3′-deoxythymidine (AZT), 2′,3′-dideoxyinosine (ddI),2′,3′-dideoxy-3′-thiacytidine (3TC),2′,3′-didehydro-2′,3′-dideoxythymidine (d4T) and the monophosphatenucleotides of 3′-azido-3′-deoxythymidine (AZT),2′,3′-dideoxy-3′-thiacytidine (3TC) and2′,3′-didehydro-2′,3′-dideoxythymidine (d4T). In one embodiment,deoxynucleotides are used as the modifiers. When nucleotide modifiersare utilized, 1-3 nucleotide modifiers, or 2 nucleotide modifiers aresubstituted for the ribonucleotides on the 3′ end of the antisensestrand. When sterically hindered molecules are utilized, they areattached to the ribonucleotide at the 3′ end of the antisense strand.Thus, the length of the strand does not change with the incorporation ofthe modifiers. In another embodiment, the invention contemplatessubstituting two DNA bases in the dsRNA to direct the orientation ofDicer processing. In a further invention, two terminal DNA bases arelocated on the 3′ end of the antisense strand in place of tworibonucleotides forming a blunt end of the duplex on the 5′ end of thesense strand and the 3′ end of the antisense strand, and atwo-nucleotide RNA overhang is located on the 3′-end of the sensestrand. This is also an asymmetric composition with DNA on the blunt endand RNA bases on the overhanging end.

The sense and antisense strands anneal under biological conditions, suchas the conditions found in the cytoplasm of a cell. In addition, aregion of one of the sequences, particularly of the antisense strand, ofthe dsRNA has a sequence length of at least 19 nucleotides, whereinthese nucleotides are adjacent to the 3′ end of antisense strand and aresufficiently complementary to a nucleotide sequence of the target α-1antitrypsin RNA.

Additionally, the DsiRNA agent structure can be optimized to ensure thatthe oligonucleotide segment generated from Dicer's cleavage will be theportion of the oligonucleotide that is most effective in inhibiting geneexpression. For example, in one embodiment of the invention, a 27-bpoligonucleotide of the DsiRNA agent structure is synthesized wherein theanticipated 21 to 22-bp segment that will inhibit gene expression islocated on the 3′-end of the antisense strand. The remaining baseslocated on the 5′-end of the antisense strand will be cleaved by Dicerand will be discarded. This cleaved portion can be homologous (i.e.,based on the sequence of the target sequence) or non-homologous andadded to extend the nucleic acid strand.

US 2007/0265220 discloses that 27mer DsiRNAs showed improved stabilityin serum over comparable 21mer siRNA compositions, even absent chemicalmodification. Modifications of DsiRNA agents, such as inclusion of2′-O-methyl RNA in the antisense strand, in patterns such as detailedabove, when coupled with addition of a 5′ Phosphate, can improvestability of DsiRNA agents. Addition of 5′-phosphate to all strands insynthetic RNA duplexes may be an inexpensive and physiological method toconfer some limited degree of nuclease stability.

The chemical modification patterns of the dsRNA agents of the instantinvention are designed to enhance the efficacy of such agents.Accordingly, such modifications are designed to avoid reducing potencyof dsRNA agents; to avoid interfering with Dicer processing of DsiRNAagents; to improve stability in biological fluids (reduce nucleasesensitivity) of dsRNA agents; or to block or evade detection by theinnate immune system. Such modifications are also designed to avoidbeing toxic and to avoid increasing the cost or impact the ease ofmanufacturing the instant dsRNA agents of the invention.

In certain embodiments of the present invention, an anti-α-1 antitrypsinDsiRNA agent has one or more of the following properties: (i) the DsiRNAagent is asymmetric, e.g., has a 3′ overhang on the antisense strand and(ii) the DsiRNA agent has a modified 3′ end on the sense strand todirect orientation of Dicer binding and processing of the dsRNA to anactive siRNA. According to this embodiment, the longest strand in thedsRNA comprises 25-35 nucleotides (e.g., 25, 26, 27, 28, 29, 30, 31, 32,33, 34 or 35 nucleotides). In certain such embodiments, the DsiRNA agentis asymmetric such that the sense strand comprises 25-34 nucleotides andthe 3′ end of the sense strand forms a blunt end with the 5′ end of theantisense strand while the antisense strand comprises 26-35 nucleotidesand forms an overhang on the 3′ end of the antisense strand. In oneembodiment, the DsiRNA agent is asymmetric such that the sense strandcomprises 25-28 nucleotides and the antisense strand comprises 25-30nucleotides. Thus, the resulting dsRNA has an overhang on the 3′ end ofthe antisense strand. The overhang is 1˜4 nucleotides, for example 2nucleotides. The sense strand may also have a 5′ phosphate.

The DsiRNA agent can also have one or more of the following additionalproperties: (a) the antisense strand has a right shift from the typical21mer (e.g., the DsiRNA comprises a length of antisense strandnucleotides that extends to the 5′ of a projected Dicer cleavage sitewithin the DsiRNA, with such antisense strand nucleotides base pairedwith corresponding nucleotides of the sense strand extending 3′ of aprojected Dicer cleavage site in the sense strand), (b) the strands maynot be completely complementary, i.e., the strands may contain simplemismatched base pairs (in certain embodiments, the DsiRNAs of theinvention possess 1, 2, 3, 4 or even 5 or more mismatched base pairs,provided that α-1 antitrypsin inhibitory activity of the DsiRNApossessing mismatched base pairs is retained at sufficient levels (e.g.,retains at least 50% α-1 antitrypsin inhibitory activity or more, atleast 60% α-1 antitrypsin inhibitory activity or more, at least 70% α-1antitrypsin inhibitory activity or more, at least 80% α-1 antitrypsininhibitory activity or more, at least 90% α-1 antitrypsin inhibitoryactivity or more or at least 95% α-1 antitrypsin inhibitory activity ormore as compared to a corresponding DsiRNA not possessing mismatchedbase pairs. In certain embodiments, mismatched base pairs exist betweenthe antisense and sense strands of a DsiRNA. In some embodiments,mismatched base pairs exist (or are predicted to exist) between theantisense strand and the target RNA. In certain embodiments, thepresence of a mismatched base pair(s) between an antisense strandresidue and a corresponding residue within the target RNA that islocated 3′ in the target RNA sequence of a projected Ago2 cleavage siteretains and may even enhance α-1 antitrypsin inhibitory activity of aDsiRNA of the invention) and (c) base modifications such as lockednucleic acid(s) may be included in the 5′ end of the sense strand. A“typical” 21mer siRNA is designed using conventional techniques. In onetechnique, a variety of sites are commonly tested in parallel or poolscontaining several distinct siRNA duplexes specific to the same targetwith the hope that one of the reagents will be effective (Ji et al.,2003, FEBS Lett 552: 247-252). Other techniques use design rules andalgorithms to increase the likelihood of obtaining active RNAi effectormolecules (Schwarz et al., 2003, Cell 115: 199-208; Khvorova et al.,2003, Cell 115: 209-216; Ui-Tei et al., 2004, Nucleic Acids Res 32:936-948; Reynolds et al., 2004, Nat Biotechnol 22: 326-330; Krol et al.,2004, J Biol Chem 279: 42230-42239; Yuan et al., 2004, Nucl Acids Res32(Webserver issue):W130-134; Boese et al., 2005, Methods Enzymol 392:73-96). High throughput selection of siRNA has also been developed (U.S.published patent application No. 2005/0042641 A1). Potential targetsites can also be analyzed by secondary structure predictions (Heale etal., 2005, Nucleic Acids Res 33(3): e30). This 21mer is then used todesign a right shift to include 3-9 additional nucleotides on the 5′ endof the 21mer. The sequence of these additional nucleotides is notrestricted. In one embodiment, the added ribonucleotides are based onthe sequence of the target gene. Even in this embodiment, fullcomplementarity between the target sequence and the antisense siRNA isnot required.

The first and second oligonucleotides of a DsiRNA agent of the instantinvention are not required to be completely complementary. They onlyneed to be sufficiently complementary to anneal under biologicalconditions and to provide a substrate for Dicer that produces a siRNAsufficiently complementary to the target sequence. Locked nucleic acids,or LNA's, are well known to a skilled artisan (Elmen et al., 2005,Nucleic Acids Res 33: 439-447; Kurreck et al., 2002, Nucleic Acids Res30: 1911-1918; Crinelli et al., 2002, Nucleic Acids Res 30: 2435-2443;Braasch and Corey, 2001, Chem Biol 8: 1-7; Bondensgaard et al., 2000,Chemistry 6: 2687-2695; Wahlestedt et al., 2000, Proc Natl Acad Sci USA97: 5633-5638). In one embodiment, an LNA is incorporated at the 5′terminus of the sense strand. In another embodiment, an LNA isincorporated at the 5′ terminus of the sense strand in duplexes designedto include a 3′ overhang on the antisense strand.

In certain embodiments, the DsiRNA agent of the instant invention has anasymmetric structure, with the sense strand having a 25-base pairlength, and the antisense strand having a 27-base pair length with a 2base 3′-overhang. In other embodiments, this DsiRNA agent having anasymmetric structure further contains 2 deoxynucleotides at the 3′ endof the sense strand in place of two of the ribonucleotides.

Certain DsiRNA agent compositions containing two separateoligonucleotides can be linked by a third structure. The third structurewill not block Dicer activity on the DsiRNA agent and will not interferewith the directed destruction of the RNA transcribed from the targetgene. In one embodiment, the third structure may be a chemical linkinggroup. Many suitable chemical linking groups are known in the art andcan be used. Alternatively, the third structure may be anoligonucleotide that links the two oligonucleotides of the DsiRNA agentin a manner such that a hairpin structure is produced upon annealing ofthe two oligonucleotides making up the dsRNA composition. The hairpinstructure will not block Dicer activity on the DsiRNA agent and will notinterfere with the directed destruction of the α-1 antitrypsin RNA.

In Vitro Assay to Assess dsRNA α-1 Antitrypsin Inhibitory Activity

An in vitro assay that recapitulates RNAi in a cell-free system can beused to evaluate dsRNA constructs targeting α-1 antitrypsin RNAsequence(s), and thus to assess α-1 antitrypsin-specific gene inhibitoryactivity (also referred to herein as α-1 antitrypsin inhibitoryactivity) of a dsRNA. The assay comprises the system described by Tuschlet al., 1999, Genes and Development, 13, 3191-3197 and Zamore et al.,2000, Cell, 101, 25-33 adapted for use with dsRNA (e.g., DsiRNA) agentsdirected against α-1 antitrypsin RNA. A Drosophila extract derived fromsyncytial blastoderm is used to reconstitute RNAi activity in vitro.Target RNA is generated via in vitro transcription from a selected α-1antitrypsin expressing plasmid using T7 RNA polymerase or via chemicalsynthesis. Sense and antisense dsRNA strands (for example, 20 uM each)are annealed by incubation in buffer (such as 100 mM potassium acetate,30 mM HEPES-KOH, pH 7.4, 2 mM magnesium acetate) for 1 minute at 90° C.followed by 1 hour at 37° C., then diluted in lysis buffer (for example100 mM potassium acetate, 30 mM HEPES-KOH at pH 7.4, 2 mM magnesiumacetate). Annealing can be monitored by gel electrophoresis on anagarose gel in TBE buffer and stained with ethidium bromide. TheDrosophila lysate is prepared using zero to two-hour-old embryos fromOregon R flies collected on yeasted molasses agar that are dechorionatedand lysed. The lysate is centrifuged and the supernatant isolated. Theassay comprises a reaction mixture containing 50% lysate [vol/vol], RNA(10-50 pM final concentration), and 10% [vol/vol] lysis buffercontaining dsRNA (10 nM final concentration). The reaction mixture alsocontains 10 mM creatine phosphate, 10 ug/ml creatine phosphokinase, 100um GTP, 100 uM UTP, 100 uM CTP, 500 uM ATP, 5 mM DTT, 0.1 U/uL RNasin(Promega), and 100 uM of each amino acid. The final concentration ofpotassium acetate is adjusted to 100 mM. The reactions are pre-assembledon ice and preincubated at 25° C. for 10 minutes before adding RNA, thenincubated at 25° C. for an additional 60 minutes. Reactions are quenchedwith 4 volumes of 1.25×Passive Lysis Buffer (Promega). Target RNAcleavage is assayed by RT-PCR analysis or other methods known in the artand are compared to control reactions in which dsRNA is omitted from thereaction.

Alternately, internally-labeled target RNA for the assay is prepared byin vitro transcription in the presence of [α-³²P] CTP, passed over a G50Sephadex column by spin chromatography and used as target RNA withoutfurther purification. Optionally, target RNA is 5′-³²P-end labeled usingT4 polynucleotide kinase enzyme. Assays are performed as described aboveand target RNA and the specific RNA cleavage products generated by RNAiare visualized on an autoradiograph of a gel. The percentage of cleavageis determined by PHOSPHOR IMAGER® (autoradiography) quantitation ofbands representing intact control RNA or RNA from control reactionswithout dsRNA and the cleavage products generated by the assay.

In one embodiment, this assay is used to determine target sites in theα-1 antitrypsin RNA target for dsRNA mediated RNAi cleavage, wherein aplurality of dsRNA constructs are screened for RNAi mediated cleavage ofthe α-1 antitrypsin RNA target, for example, by analyzing the assayreaction by electrophoresis of labeled target RNA, or by northernblotting, as well as by other methodology well known in the art.

In certain embodiments, a dsRNA of the invention is deemed to possessα-1 antitrypsin inhibitory activity if, e.g., a 50% reduction in α-1antitrypsin RNA levels is observed in a system, cell, tissue ororganism, relative to a suitable control. Additional metes and boundsfor determination of α-1 antitrypsin inhibitory activity of a dsRNA ofthe invention are described supra.

Conjugation and Delivery of Anti-α-1 Antitrypsin dsRNA Agents

In certain embodiments the present invention relates to a method fortreating a subject having a α-1 antitrypsin-associated disease ordisorder, or at risk of developing a α-1 antitrypsin-associated diseaseor disorder. In such embodiments, the dsRNA can act as novel therapeuticagents for controlling the α-1 antitrypsin-associated disease ordisorder. The method comprises administering a pharmaceuticalcomposition of the invention to the patient (e.g., human), such that theexpression, level and/or activity of a α-1 antitrypsin RNA is reduced.The expression, level and/or activity of a polypeptide encoded by a α-1antitrypsin RNA might also be reduced by a dsRNA of the instantinvention, even where said dsRNA is directed against a non-coding regionof the α-1 antitrypsin transcript (e.g., a targeted 5′ UTR or 3′ UTRsequence). Because of their high specificity, the dsRNAs of the presentinvention can specifically target α-1 antitrypsin sequences of cells andtissues, optionally in an allele-specific manner where polymorphicalleles exist within an individual and/or population.

In the treatment of a α-1 antitrypsin-associated disease or disorder,the dsRNA can be brought into contact with the cells or tissue of asubject, e.g., the cells or tissue of a subject exhibiting disregulationof α-1 antitrypsin and/or otherwise targeted for reduction of α-1antitrypsin levels. For example, dsRNA substantially identical to all orpart of a α-1 antitrypsin RNA sequence, may be brought into contact withor introduced into such a cell, either in vivo or in vitro. Similarly,dsRNA substantially identical to all or part of a α-1 antitrypsin RNAsequence may administered directly to a subject having or at risk ofdeveloping a α-1 antitrypsin-associated disease or disorder.

Therapeutic use of the dsRNA agents of the instant invention can involveuse of formulations of dsRNA agents comprising multiple different dsRNAagent sequences. For example, two or more, three or more, four or more,five or more, etc. of the presently described agents can be combined toproduce a formulation that, e.g., targets multiple different regions ofthe α-1 antitrypsin RNA, or that not only target α-1 antitrypsin RNA butalso target, e.g., cellular target genes associated with a α-1antitrypsin-associated disease or disorder. A dsRNA agent of the instantinvention may also be constructed such that either strand of the dsRNAagent independently targets two or more regions of α-1 antitrypsin RNA,or such that one of the strands of the dsRNA agent targets a cellulartarget gene of α-1 antitrypsin known in the art.

Use of multifunctional dsRNA molecules that target more then one regionof a target nucleic acid molecule can also provide potent inhibition ofα-1 antitrypsin RNA levels and expression. For example, a singlemultifunctional dsRNA construct of the invention can target both the α-1antitrypsin-506 and α-1 antitrypsin-1059 sites simultaneously;additionally and/or alternatively, single or multifunctional agents ofthe invention can be designed to selectively target one splice variantof α-1 antitrypsin over another.

Thus, the dsRNA agents of the instant invention, individually, or incombination or in conjunction with other drugs, can be used to treat,inhibit, reduce, or prevent a α-1 antitrypsin-associated disease ordisorder. For example, the dsRNA molecules can be administered to asubject or can be administered to other appropriate cells evident tothose skilled in the art, individually or in combination with one ormore drugs under conditions suitable for the treatment.

The dsRNA molecules also can be used in combination with other knowntreatments to treat, inhibit, reduce, or prevent a α-1antitrypsin-associated disease or disorder in a subject or organism. Forexample, the described molecules could be used in combination with oneor more known compounds, treatments, or procedures to treat, inhibit,reduce, or prevent a α-1 antitrypsin-associated disease or disorder in asubject or organism as are known in the art.

A dsRNA agent of the invention can be conjugated (e.g., at its 5′ or 3′terminus of its sense or antisense strand) or unconjugated to anothermoiety (e.g. a non-nucleic acid moiety such as a peptide), an organiccompound (e.g., a dye, cholesterol, or the like). Modifying dsRNA agentsin this way may improve cellular uptake or enhance cellular targetingactivities of the resulting dsRNA agent derivative as compared to thecorresponding unconjugated dsRNA agent, are useful for tracing the dsRNAagent derivative in the cell, or improve the stability of the dsRNAagent derivative compared to the corresponding unconjugated dsRNA agent.

Methods of Introducing Nucleic Acids, Vectors, and Host Cells

dsRNA agents of the invention may be directly introduced into a cell(i.e., intracellularly); or introduced extracellularly into a cavity,interstitial space, into the circulation of an organism, introducedorally, or may be introduced by bathing a cell or organism in a solutioncontaining the nucleic acid. Vascular or extravascular circulation, theblood or lymph system, and the cerebrospinal fluid are sites where thenucleic acid may be introduced.

The dsRNA agents of the invention can be introduced using nucleic aciddelivery methods known in art including injection of a solutioncontaining the nucleic acid, bombardment by particles covered by thenucleic acid, soaking the cell or organism in a solution of the nucleicacid, or electroporation of cell membranes in the presence of thenucleic acid. Other methods known in the art for introducing nucleicacids to cells may be used, such as lipid-mediated carrier transport,chemical-mediated transport, and cationic liposome transfection such ascalcium phosphate, and the like. The nucleic acid may be introducedalong with other components that perform one or more of the followingactivities: enhance nucleic acid uptake by the cell or otherwiseincrease inhibition of the target α-1 antitrypsin RNA.

A cell having a target α-1 antitrypsin RNA may be from the germ line orsomatic, totipotent or pluripotent, dividing or non-dividing, parenchymaor epithelium, immortalized or transformed, or the like. The cell may bea stem cell or a differentiated cell. Cell types that are differentiatedinclude adipocytes, fibroblasts, myocytes, cardiomyocytes, endothelium,neurons, glia, blood cells, megakaryocytes, lymphocytes, macrophages,neutrophils, eosinophils, basophils, mast cells, leukocytes,granulocytes, keratinocytes, chondrocytes, osteoblasts, osteoclasts,hepatocytes, and cells of the endocrine or exocrine glands.

Depending on the particular target α-1 antitrypsin RNA sequence and thedose of dsRNA agent material delivered, this process may provide partialor complete loss of function for the α-1 antitrypsin RNA. A reduction orloss of RNA levels or expression (either α-1 antitrypsin RNA expressionor encoded polypeptide expression) in at least 50%, 60%, 70%, 80%, 90%,95% or 99% or more of targeted cells is exemplary. Inhibition of α-1antitrypsin RNA levels or expression refers to the absence (orobservable decrease) in the level of α-1 antitrypsin RNA or α-1antitrypsin RNA-encoded protein. Specificity refers to the ability toinhibit the α-1 antitrypsin RNA without manifest effects on other genesof the cell. The consequences of inhibition can be confirmed byexamination of the outward properties of the cell or organism or bybiochemical techniques such as RNA solution hybridization, nucleaseprotection, Northern hybridization, reverse transcription, geneexpression monitoring with a microarray, antibody binding, enzyme linkedimmunosorbent assay (ELISA), Western blotting, radioimmunoassay (RIA),other immunoassays, and fluorescence activated cell analysis (FACS).Inhibition of target α-1 antitrypsin RNA sequence(s) by the dsRNA agentsof the invention also can be measured based upon the effect ofadministration of such dsRNA agents upon development/progression of anα-1 antitrypsin-associated disease or disorder, e.g., chronic liverdisease, liver inflammation, cirrhosis, liver fibrosis, and/orhepatocellular carcinoma, etc., either in vivo or in vitro. Treatment ofany of these preceding liver conditions can be assessed byart-recognized tests for liver function, e.g., determination of thepercentage of liver function (e.g., 20%, 30%, 40%, 50%, 60%, 70%, 80% orgreater) that is being achieved relative to average healthy liverfunction of an appropriate control population. In certain embodiments,successful treatment result in a decline or halting of reduction intotal liver function associated with a liver disease. In someembodiments, liver function improves with successful treatment.Treatment and/or reductions in hepatocellular carcinoma tumor or cancercell levels can include halting or reduction of growth of tumor orcancer cell levels or reductions of, e.g., 10%, 20%, 30%, 40%, 50%, 60%,70%, 80%, 90%, 95% or 99% or more, and can also be measured inlogarithmic terms, e.g., 10-fold, 100-fold, 1000-fold, 10⁵-fold,10⁶-fold, 10⁷-fold reduction in cancer cell levels could be achieved viaadministration of the dsRNA agents of the invention to cells, a tissue,or a subject.

For RNA-mediated inhibition in a cell line or whole organism, expressiona reporter or drug resistance gene whose protein product is easilyassayed can be measured. Such reporter genes include acetohydroxyacidsynthase (AHAS), alkaline phosphatase (AP), beta galactosidase (LacZ),beta glucoronidase (GUS), chloramphenicol acetyltransferase (CAT), greenfluorescent protein (GFP), horseradish peroxidase (HRP), luciferase(Luc), nopaline synthase (NOS), octopine synthase (OCS), and derivativesthereof. Multiple selectable markers are available that conferresistance to ampicillin, bleomycin, chloramphenicol, gentamycin,hygromycin, kanamycin, lincomycin, methotrexate, phosphinothricin,puromycin, and tetracyclin. Depending on the assay, quantitation of theamount of gene expression allows one to determine a degree of inhibitionwhich is greater than 10%, 33%, 50%, 90%, 95% or 99% as compared to acell not treated according to the present invention.

Lower doses of injected material and longer times after administrationof RNA silencing agent may result in inhibition in a smaller fraction ofcells (e.g., at least 10%, 20%, 50%, 75%, 90%, or 95% of targetedcells). Quantitation of gene expression in a cell may show similaramounts of inhibition at the level of accumulation of target α-1antitrypsin RNA or translation of target protein. As an example, theefficiency of inhibition may be determined by assessing the amount ofgene product in the cell; RNA may be detected with a hybridization probehaving a nucleotide sequence outside the region used for the inhibitorydsRNA, or translated polypeptide may be detected with an antibody raisedagainst the polypeptide sequence of that region.

The dsRNA agent may be introduced in an amount which allows delivery ofat least one copy per cell. Higher doses (e.g., at least 5, 10, 100, 500or 1000 copies per cell) of material may yield more effectiveinhibition; lower doses may also be useful for specific applications.

Pharmaceutical Compositions

In certain embodiments, the present invention provides for apharmaceutical composition comprising the dsRNA agent of the presentinvention. The dsRNA agent sample can be suitably formulated andintroduced into the environment of the cell by any means that allows fora sufficient portion of the sample to enter the cell to induce genesilencing, if it is to occur. Many formulations for dsRNA are known inthe art and can be used so long as the dsRNA gains entry to the targetcells so that it can act. See, e.g., U.S. published patent applicationNos. 2004/0203145 A1 and 2005/0054598 A1. For example, the dsRNA agentof the instant invention can be formulated in buffer solutions such asphosphate buffered saline solutions, liposomes, micellar structures, andcapsids. Formulations of dsRNA agent with cationic lipids can be used tofacilitate transfection of the dsRNA agent into cells. For example,cationic lipids, such as lipofectin (U.S. Pat. No. 5,705,188), cationicglycerol derivatives, and polycationic molecules, such as polylysine(published PCT International Application WO 97/30731), can be used.Suitable lipids include Oligofectamine, Lipofectamine (LifeTechnologies), NC388 (Ribozyme Pharmaceuticals, Inc., Boulder, Colo.),or FuGene 6 (Roche) all of which can be used according to themanufacturer's instructions.

Such compositions typically include the nucleic acid molecule and apharmaceutically acceptable carrier. As used herein the language“pharmaceutically acceptable carrier” includes saline, solvents,dispersion media, coatings, antibacterial and antifungal agents,isotonic and absorption delaying agents, and the like, compatible withpharmaceutical administration. Supplementary active compounds can alsobe incorporated into the compositions.

A pharmaceutical composition is formulated to be compatible with itsintended route of administration. Examples of routes of administrationinclude parenteral, e.g., intravenous, intradermal, subcutaneous, oral(e.g., inhalation), transdermal (topical), transmucosal, and rectaladministration. Solutions or suspensions used for parenteral,intradermal, or subcutaneous application can include the followingcomponents: a sterile diluent such as water for injection, salinesolution, fixed oils, polyethylene glycols, glycerine, propylene glycolor other synthetic solvents; antibacterial agents such as benzyl alcoholor methyl parabens; antioxidants such as ascorbic acid or sodiumbisulfite; chelating agents such as ethylenediaminetetraacetic acid;buffers such as acetates, citrates or phosphates and agents for theadjustment of tonicity such as sodium chloride or dextrose. pH can beadjusted with acids or bases, such as hydrochloric acid or sodiumhydroxide. The parenteral preparation can be enclosed in ampoules,disposable syringes or multiple dose vials made of glass or plastic.

Pharmaceutical compositions suitable for injectable use include sterileaqueous solutions (where water soluble) or dispersions and sterilepowders for the extemporaneous preparation of sterile injectablesolutions or dispersion. For intravenous administration, suitablecarriers include physiological saline, bacteriostatic water, CremophorEL™ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In allcases, the composition must be sterile and should be fluid to the extentthat easy syringability exists. It should be stable under the conditionsof manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (for example, glycerol, propylene glycol, andliquid polyetheylene glycol, and the like), and suitable mixturesthereof. The proper fluidity can be maintained, for example, by the useof a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersion and by the use of surfactants.Prevention of the action of microorganisms can be achieved by variousantibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In manycases, it will be preferable to include isotonic agents, for example,sugars, polyalcohols such as manitol, sorbitol, sodium chloride in thecomposition. Prolonged absorption of the injectable compositions can bebrought about by including in the composition an agent which delaysabsorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions can be prepared by incorporating the activecompound in the required amount in a selected solvent with one or acombination of ingredients enumerated above, as required, followed byfiltered sterilization. Generally, dispersions are prepared byincorporating the active compound into a sterile vehicle, which containsa basic dispersion medium and the required other ingredients from thoseenumerated above. In the case of sterile powders for the preparation ofsterile injectable solutions, the preferred methods of preparation arevacuum drying and freeze-drying which yields a powder of the activeingredient plus any additional desired ingredient from a previouslysterile-filtered solution thereof.

Oral compositions generally include an inert diluent or an ediblecarrier. For the purpose of oral therapeutic administration, the activecompound can be incorporated with excipients and used in the form oftablets, troches, or capsules, e.g., gelatin capsules. Oral compositionscan also be prepared using a fluid carrier for use as a mouthwash.Pharmaceutically compatible binding agents, and/or adjuvant materialscan be included as part of the composition. The tablets, pills,capsules, troches and the like can contain any of the followingingredients, or compounds of a similar nature: a binder such asmicrocrystalline cellulose, gum tragacanth or gelatin; an excipient suchas starch or lactose, a disintegrating agent such as alginic acid,Primogel, or corn starch; a lubricant such as magnesium stearate orSterotes; a glidant such as colloidal silicon dioxide; a sweeteningagent such as sucrose or saccharin; or a flavoring agent such aspeppermint, methyl salicylate, or orange flavoring.

For administration by inhalation, the compounds are delivered in theform of an aerosol spray from pressured container or dispenser whichcontains a suitable propellant, e.g., a gas such as carbon dioxide, or anebulizer. Such methods include those described in U.S. Pat. No.6,468,798.

Systemic administration can also be by transmucosal or transdermalmeans. For transmucosal or transdermal administration, penetrantsappropriate to the barrier to be permeated are used in the formulation.Such penetrants are generally known in the art, and include, forexample, for transmucosal administration, detergents, bile salts, andfusidic acid derivatives. Transmucosal administration can beaccomplished through the use of nasal sprays or suppositories. Fortransdermal administration, the active compounds are formulated intoointments, salves, gels, or creams as generally known in the art.

The compounds can also be prepared in the form of suppositories (e.g.,with conventional suppository bases such as cocoa butter and otherglycerides) or retention enemas for rectal delivery.

The compounds can also be administered by transfection or infectionusing methods known in the art, including but not limited to the methodsdescribed in McCaffrey et al. (2002), Nature, 418(6893), 38-9(hydrodynamic transfection); Xia et al. (2002), Nature Biotechnol.,20(10), 1006-10 (viral-mediated delivery); or Putnam (1996), Am. J.Health Syst. Pharm. 53(2), 151-160, erratum at Am. J. Health Syst.Pharm. 53(3), 325 (1996).

The compounds can also be administered by a method suitable foradministration of nucleic acid agents, such as a DNA vaccine. Thesemethods include gene guns, bio injectors, and skin patches as well asneedle-free methods such as the micro-particle DNA vaccine technologydisclosed in U.S. Pat. No. 6,194,389, and the mammalian transdermalneedle-free vaccination with powder-form vaccine as disclosed in U.S.Pat. No. 6,168,587. Additionally, intranasal delivery is possible, asdescribed in, inter alia, Hamajima et al. (1998), Clin. Immunol.Immunopathol., 88(2), 205-10. Liposomes (e.g., as described in U.S. Pat.No. 6,472,375) and microencapsulation can also be used. Biodegradabletargetable microparticle delivery systems can also be used (e.g., asdescribed in U.S. Pat. No. 6,471,996).

In one embodiment, the active compounds are prepared with carriers thatwill protect the compound against rapid elimination from the body, suchas a controlled release formulation, including implants andmicroencapsulated delivery systems. Biodegradable, biocompatiblepolymers can be used, such as ethylene vinyl acetate, polyanhydrides,polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Suchformulations can be prepared using standard techniques. The materialscan also be obtained commercially from Alza Corporation and NovaPharmaceuticals, Inc. Liposomal suspensions (including liposomestargeted to infected cells with monoclonal antibodies to viral antigens)can also be used as pharmaceutically acceptable carriers. These can beprepared according to methods known to those skilled in the art, forexample, as described in U.S. Pat. No. 4,522,811.

Toxicity and therapeutic efficacy of such compounds can be determined bystandard pharmaceutical procedures in cell cultures or experimentalanimals, e.g., for determining the LD₅₀ (the dose lethal to 50% of thepopulation) and the ED₅₀ (the dose therapeutically effective in 50% ofthe population). The dose ratio between toxic and therapeutic effects isthe therapeutic index and it can be expressed as the ratio LD₅₀/ED₅₀.Compounds which exhibit high therapeutic indices are preferred. Whilecompounds that exhibit toxic side effects may be used, care should betaken to design a delivery system that targets such compounds to thesite of affected tissue in order to minimize potential damage touninfected cells and, thereby, reduce side effects.

The data obtained from the cell culture assays and animal studies can beused in formulating a range of dosage for use in humans. The dosage ofsuch compounds lies preferably within a range of circulatingconcentrations that include the ED₅₀ with little or no toxicity. Thedosage may vary within this range depending upon the dosage formemployed and the route of administration utilized. For a compound usedin the method of the invention, the therapeutically effective dose canbe estimated initially from cell culture assays. A dose may beformulated in animal models to achieve a circulating plasmaconcentration range that includes the IC₅₀ (i.e., the concentration ofthe test compound which achieves a half-maximal inhibition of symptoms)as determined in cell culture. Such information can be used to moreaccurately determine useful doses in humans. Levels in plasma may bemeasured, for example, by high performance liquid chromatography.

As defined herein, a therapeutically effective amount of a nucleic acidmolecule (i.e., an effective dosage) depends on the nucleic acidselected. For instance, single dose amounts of a dsRNA (or, e.g., aconstruct(s) encoding for such dsRNA) in the range of approximately 1 pgto 1000 mg may be administered; in some embodiments, 10, 30, 100, or1000 pg, or 10, 30, 100, or 1000 ng, or 10, 30, 100, or 1000 μg, or 10,30, 100, or 1000 mg may be administered. In some embodiments, 1-5 g ofthe compositions can be administered. The compositions can beadministered one from one or more times per day to one or more times perweek; including once every other day. The skilled artisan willappreciate that certain factors may influence the dosage and timingrequired to effectively treat a subject, including but not limited tothe severity of the disease or disorder, previous treatments, thegeneral health and/or age of the subject, and other diseases present.Moreover, treatment of a subject with a therapeutically effective amountof a nucleic acid (e.g., dsRNA), protein, polypeptide, or antibody caninclude a single treatment or, preferably, can include a series oftreatments.

The nucleic acid molecules of the invention can be inserted intoexpression constructs, e.g., viral vectors, retroviral vectors,expression cassettes, or plasmid viral vectors, e.g., using methodsknown in the art, including but not limited to those described in Xia etal., (2002), supra. Expression constructs can be delivered to a subjectby, for example, inhalation, orally, intravenous injection, localadministration (see U.S. Pat. No. 5,328,470) or by stereotacticinjection (see e.g., Chen et al. (1994), Proc. Natl. Acad. Sci. USA, 91,3054-3057). The pharmaceutical preparation of the delivery vector caninclude the vector in an acceptable diluent, or can comprise a slowrelease matrix in which the delivery vehicle is imbedded. Alternatively,where the complete delivery vector can be produced intact fromrecombinant cells, e.g., retroviral vectors, the pharmaceuticalpreparation can include one or more cells which produce the genedelivery system.

The expression constructs may be constructs suitable for use in theappropriate expression system and include, but are not limited toretroviral vectors, linear expression cassettes, plasmids and viral orvirally-derived vectors, as known in the art. Such expression constructsmay include one or more inducible promoters, RNA Pol III promotersystems such as U6 snRNA promoters or H1 RNA polymerase III promoters,or other promoters known in the art. The constructs can include one orboth strands of the siRNA. Expression constructs expressing both strandscan also include loop structures linking both strands, or each strandcan be separately transcribed from separate promoters within the sameconstruct. Each strand can also be transcribed from a separateexpression construct, e.g., Tuschl (2002, Nature Biotechnol 20:500-505).

It can be appreciated that the method of introducing dsRNA agents intothe environment of the cell will depend on the type of cell and the makeup of its environment. For example, when the cells are found within aliquid, one preferable formulation is with a lipid formulation such asin lipofectamine and the dsRNA agents can be added directly to theliquid environment of the cells. Lipid formulations can also beadministered to animals such as by intravenous, intramuscular, orintraperitoneal injection, or orally or by inhalation or other methodsas are known in the art. When the formulation is suitable foradministration into animals such as mammals and more specificallyhumans, the formulation is also pharmaceutically acceptable.Pharmaceutically acceptable formulations for administeringoligonucleotides are known and can be used. In some instances, it may bepreferable to formulate dsRNA agents in a buffer or saline solution anddirectly inject the formulated dsRNA agents into cells, as in studieswith oocytes. The direct injection of dsRNA agent duplexes may also bedone. For suitable methods of introducing dsRNA (e.g., DsiRNA agents),see U.S. published patent application No. 2004/0203145 A1.

Suitable amounts of a dsRNA agent must be introduced and these amountscan be empirically determined using standard methods. Typically,effective concentrations of individual dsRNA agent species in theenvironment of a cell will be 50 nanomolar or less, 10 nanomolar orless, or compositions in which concentrations of 1 nanomolar or less canbe used. In another embodiment, methods utilizing a concentration of 200picomolar or less, 100 picomolar or less, 50 picomolar or less, 20picomolar or less, and even a concentration of 10 picomolar or less, 5picomolar or less, 2 picomolar or less or 1 picomolar or less can beused in many circumstances.

The method can be carried out by addition of the dsRNA agentcompositions to an extracellular matrix in which cells can live providedthat the dsRNA agent composition is formulated so that a sufficientamount of the dsRNA agent can enter the cell to exert its effect. Forexample, the method is amenable for use with cells present in a liquidsuch as a liquid culture or cell growth media, in tissue explants, or inwhole organisms, including animals, such as mammals and especiallyhumans.

The level or activity of a α-1 antitrypsin RNA can be determined by asuitable method now known in the art or that is later developed. It canbe appreciated that the method used to measure a target RNA and/or theexpression of a target RNA can depend upon the nature of the target RNA.For example, where the target α-1 antitrypsin RNA sequence encodes aprotein, the term “expression” can refer to a protein or the α-1antitrypsin RNA/transcript derived from the α-1 antitrypsin gene (eithergenomic or of exogenous origin). In such instances the expression of thetarget α-1 antitrypsin RNA can be determined by measuring the amount ofα-1 antitrypsin RNA/transcript directly or by measuring the amount ofα-1 antitrypsin protein. Protein can be measured in protein assays suchas by staining or immunoblotting or, if the protein catalyzes a reactionthat can be measured, by measuring reaction rates. All such methods areknown in the art and can be used. Where target α-1 antitrypsin RNAlevels are to be measured, art-recognized methods for detecting RNAlevels can be used (e.g., RT-PCR, Northern Blotting, etc.). In targetingα-1 antitrypsin RNAs with the dsRNA agents of the instant invention, itis also anticipated that measurement of the efficacy of a dsRNA agent inreducing levels of α-1 antitrypsin RNA or protein in a subject, tissue,in cells, either in vitro or in vivo, or in cell extracts can also beused to determine the extent of reduction of α-1 antitrypsin-associatedphenotypes (e.g., disease or disorders, e.g., chronic liver disease,liver inflammation, cirrhosis, liver fibrosis, and/or hepatocellularcarcinoma, etc.). The above measurements can be made on cells, cellextracts, tissues, tissue extracts or other suitable source material.

The determination of whether the expression of a α-1 antitrypsin RNA hasbeen reduced can be by a suitable method that can reliably detectchanges in RNA levels. Typically, the determination is made byintroducing into the environment of a cell undigested dsRNA such that atleast a portion of that dsRNA agent enters the cytoplasm, and thenmeasuring the level of the target RNA. The same measurement is made onidentical untreated cells and the results obtained from each measurementare compared.

The dsRNA agent can be formulated as a pharmaceutical composition whichcomprises a pharmacologically effective amount of a dsRNA agent andpharmaceutically acceptable carrier. A pharmacologically ortherapeutically effective amount refers to that amount of a dsRNA agenteffective to produce the intended pharmacological, therapeutic orpreventive result. The phrases “pharmacologically effective amount” and“therapeutically effective amount” or simply “effective amount” refer tothat amount of an RNA effective to produce the intended pharmacological,therapeutic or preventive result. For example, if a given clinicaltreatment is considered effective when there is at least a 20% reductionin a measurable parameter associated with a disease or disorder, atherapeutically effective amount of a drug for the treatment of thatdisease or disorder is the amount necessary to effect at least a 20%reduction in that parameter.

Suitably formulated pharmaceutical compositions of this invention can beadministered by means known in the art such as by parenteral routes,including intravenous, intramuscular, intraperitoneal, subcutaneous,transdermal, airway (aerosol), rectal, vaginal and topical (includingbuccal and sublingual) administration. In some embodiments, thepharmaceutical compositions are administered by intravenous orintraparenteral infusion or injection.

In general, a suitable dosage unit of dsRNA will be in the range of0.001 to 0.25 milligrams per kilogram body weight of the recipient perday, or in the range of 0.01 to 20 micrograms per kilogram body weightper day, or in the range of 0.001 to 5 micrograms per kilogram of bodyweight per day, or in the range of 1 to 500 nanograms per kilogram ofbody weight per day, or in the range of 0.01 to 10 micrograms perkilogram body weight per day, or in the range of 0.10 to 5 microgramsper kilogram body weight per day, or in the range of 0.1 to 2.5micrograms per kilogram body weight per day. A pharmaceuticalcomposition comprising the dsRNA can be administered once daily.However, the therapeutic agent may also be dosed in dosage unitscontaining two, three, four, five, six or more sub-doses administered atappropriate intervals throughout the day. In that case, the dsRNAcontained in each sub-dose must be correspondingly smaller in order toachieve the total daily dosage unit. The dosage unit can also becompounded for a single dose over several days, e.g., using aconventional sustained release formulation which provides sustained andconsistent release of the dsRNA over a several day period. Sustainedrelease formulations are well known in the art. In this embodiment, thedosage unit contains a corresponding multiple of the daily dose.Regardless of the formulation, the pharmaceutical composition mustcontain dsRNA in a quantity sufficient to inhibit expression of thetarget gene in the animal or human being treated. The composition can becompounded in such a way that the sum of the multiple units of dsRNAtogether contain a sufficient dose.

Data can be obtained from cell culture assays and animal studies toformulate a suitable dosage range for humans. The dosage of compositionsof the invention lies within a range of circulating concentrations thatinclude the ED₅₀ (as determined by known methods) with little or notoxicity. The dosage may vary within this range depending upon thedosage form employed and the route of administration utilized. For acompound used in the method of the invention, the therapeuticallyeffective dose can be estimated initially from cell culture assays. Adose may be formulated in animal models to achieve a circulating plasmaconcentration range of the compound that includes the IC₅₀ (i.e., theconcentration of the test compound which achieves a half-maximalinhibition of symptoms) as determined in cell culture. Such informationcan be used to more accurately determine useful doses in humans. Levelsof dsRNA in plasma may be measured by standard methods, for example, byhigh performance liquid chromatography.

The pharmaceutical compositions can be included in a kit, container,pack, or dispenser together with instructions for administration.

Methods of Treatment

The present invention provides for both prophylactic and therapeuticmethods of treating a subject at risk of (or susceptible to) a diseaseor disorder caused, in whole or in part, by α-1 antitrypsin (e.g.,misregulation and/or elevation of α-1 antitrypsin transcript and/or α-1antitrypsin protein levels), or treatable via selective targeting of α-1antitrypsin.

In certain aspects, the invention provides a method for preventing in asubject, a disease or disorder as described herein (including, e.g.,prevention of the commencement of transforming events within a subjectvia inhibition of α-1 antitrypsin expression), by administering to thesubject a therapeutic agent (e.g., a dsRNA agent or vector or transgeneencoding same). Subjects at risk for the disease can be identified by,for example, one or a combination of diagnostic or prognostic assays asdescribed herein. Administration of a prophylactic agent can occur priorto the detection of, e.g., cancer in a subject, or the manifestation ofsymptoms characteristic of the disease or disorder, such that thedisease or disorder is prevented or, alternatively, delayed in itsprogression.

Another aspect of the invention pertains to methods of treating subjectstherapeutically, i.e., altering the onset of symptoms of the disease ordisorder. These methods can be performed in vitro (e.g., by culturingthe cell with the dsRNA agent) or, alternatively, in vivo (e.g., byadministering the dsRNA agent to a subject).

With regard to both prophylactic and therapeutic methods of treatment,such treatments may be specifically tailored or modified, based onknowledge obtained from the field of pharmacogenomics.“Pharmacogenomics”, as used herein, refers to the application ofgenomics technologies such as gene sequencing, statistical genetics, andgene expression analysis to drugs in clinical development and on themarket. More specifically, the term refers the study of how a patient'sgenes determine his or her response to a drug (e.g., a patient's “drugresponse phenotype”, or “drug response genotype”). Thus, another aspectof the invention provides methods for tailoring an individual'sprophylactic or therapeutic treatment with either the target α-1antitrypsin RNA molecules of the present invention or target α-1antitrypsin RNA modulators according to that individual's drug responsegenotype. Pharmacogenomics allows a clinician or physician to targetprophylactic or therapeutic treatments to patients who will most benefitfrom the treatment and to avoid treatment of patients who willexperience toxic drug-related side effects.

The practice of the present invention employs, unless otherwiseindicated, conventional techniques of chemistry, molecular biology,microbiology, recombinant DNA, genetics, immunology, cell biology, cellculture and transgenic biology, which are within the skill of the art.See, e.g., Maniatis et al., 1982, Molecular Cloning (Cold Spring HarborLaboratory Press, Cold Spring Harbor, N.Y.); Sambrook et al., 1989,Molecular Cloning, 2nd Ed. (Cold Spring Harbor Laboratory Press, ColdSpring Harbor, N.Y.); Sambrook and Russell, 2001, Molecular Cloning, 3rdEd. (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.);Ausubel et al., 1992), Current Protocols in Molecular Biology (JohnWiley & Sons, including periodic updates); Glover, 1985, DNA Cloning(IRL Press, Oxford); Anand, 1992; Guthrie and Fink, 1991; Harlow andLane, 1988, Antibodies, (Cold Spring Harbor Laboratory Press, ColdSpring Harbor, N.Y.); Jakoby and Pastan, 1979; Nucleic AcidHybridization (B. D. Hames & S. J. Higgins eds. 1984); Transcription AndTranslation (B. D. Hames & S. J. Higgins eds. 1984); Culture Of AnimalCells (R. I. Freshney, Alan R. Liss, Inc., 1987); Immobilized Cells AndEnzymes (IRL Press, 1986); B. Perbal, A Practical Guide To MolecularCloning (1984); the treatise, Methods In Enzymology (Academic Press,Inc., N.Y.); Gene Transfer Vectors For Mammalian Cells (J. H. Miller andM. P. Calos eds., 1987, Cold Spring Harbor Laboratory); Methods InEnzymology, Vols. 154 and 155 (Wu et al. eds.), Immunochemical MethodsIn Cell And Molecular Biology (Mayer and Walker, eds., Academic Press,London, 1987); Handbook Of Experimental Immunology, Volumes I-IV (D. M.Weir and C. C. Blackwell, eds., 1986); Riott, Essential Immunology, 6thEdition, Blackwell Scientific Publications, Oxford, 1988; Hogan et al.,Manipulating the Mouse Embryo, (Cold Spring Harbor Laboratory Press,Cold Spring Harbor, N.Y., 1986); Westerfield, M., The zebrafish book. Aguide for the laboratory use of zebrafish (Danio rerio), (4th Ed., Univ.of Oregon Press, Eugene, 2000).

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although methods and materialssimilar or equivalent to those described herein can be used in thepractice or testing of the present invention, suitable methods andmaterials are described below. All publications, patent applications,patents, and other references mentioned herein are incorporated byreference in their entirety. In case of conflict, the presentspecification, including definitions, will control. In addition, thematerials, methods, and examples are illustrative only and not intendedto be limiting.

EXAMPLES

The present invention is described by reference to the followingExamples, which are offered by way of illustration and are not intendedto limit the invention in any manner. Standard techniques well known inthe art or the techniques specifically described below were utilized.

Example 1: Preparation of Double-Stranded RNA Oligonucleotides

Oligonucleotide Synthesis and Purification

DsiRNA molecules can be designed to interact with various sites in theRNA message, for example, target sequences within the RNA sequencesdescribed herein. In presently exemplified agents, 384 human target α-1antitrypsin sequences were selected for evaluation (a selection of the384 human target α-1 antitrypsin sites were predicted to be conservedwith corresponding sites in the mouse α-1 antitrypsin transcriptsequence). The sequences of one strand of the DsiRNA molecules werecomplementary to the target α-1 antitrypsin site sequences describedabove. The DsiRNA molecules were chemically synthesized using methodsdescribed herein. Generally, DsiRNA constructs were synthesized usingsolid phase oligonucleotide synthesis methods as described for 19-23mersiRNAs (see for example Usman et al., U.S. Pat. Nos. 5,804,683;5,831,071; 5,998,203; 6,117,657; 6,353,098; 6,362,323; 6,437,117;6,469,158; Scaringe et al., U.S. Pat. Nos. 6,111,086; 6,008,400;6,111,086).

Individual RNA strands were synthesized and HPLC purified according tostandard methods (Integrated DNA Technologies, Coralville, Iowa). Forexample, RNA oligonucleotides were synthesized using solid phasephosphoramidite chemistry, deprotected and desalted on NAP-5 columns(Amersham Pharmacia Biotech, Piscataway, N.J.) using standard techniques(Damha and Olgivie, 1993, Methods Mol Biol 20: 81-114; Wincott et al.,1995, Nucleic Acids Res 23: 2677-84). The oligomers were purified usingion-exchange high performance liquid chromatography (IE-HPLC) on anAmersham Source 15Q column (1.0 cm×25 cm; Amersham Pharmacia Biotech,Piscataway, N.J.) using a 15 min step-linear gradient. The gradientvaried from 90:10 Buffers A:B to 52:48 Buffers A:B, where Buffer A was100 mM Tris pH 8.5 and Buffer B was 100 mM Tris pH 8.5, 1 M NaCl.Samples were monitored at 260 nm and peaks corresponding to thefull-length oligonucleotide species were collected, pooled, desalted onNAP-5 columns, and lyophilized.

The purity of each oligomer was determined by capillary electrophoresis(CE) on a Beckman PACE 5000 (Beckman Coulter, Inc., Fullerton, Calif.).The CE capillaries had a 100 μm inner diameter and contained ssDNA 100RGel (Beckman-Coulter). Typically, about 0.6 nmole of oligonucleotide wasinjected into a capillary, run in an electric field of 444 V/cm anddetected by UV absorbance at 260 nm. Denaturing Tris-Borate-7 M-urearunning buffer was purchased from Beckman-Coulter. Oligoribonucleotideswere obtained that were at least 90% pure as assessed by CE for use inexperiments described below. Compound identity was verified bymatrix-assisted laser desorption ionization time-of-flight (MALDI-TOF)mass spectroscopy on a Voyager DE™ Biospectometry Work Station (AppliedBiosystems, Foster City, Calif.) following the manufacturer'srecommended protocol. Relative molecular masses of all oligomers wereobtained, often within 0.2% of expected molecular mass.

Preparation of Duplexes

Single-stranded RNA (ssRNA) oligomers were resuspended, e.g., at 100 μMconcentration in duplex buffer consisting of 100 mM potassium acetate,30 mM HEPES, pH 7.5. Complementary sense and antisense strands weremixed in equal molar amounts to yield a final solution of, e.g., 50 μMduplex. Samples were heated to 100° C. for 5′ in RNA buffer (IDT) andallowed to cool to room temperature before use. Double-stranded RNA(dsRNA) oligomers were stored at −20° C. Single-stranded RNA oligomerswere stored lyophilized or in nuclease-free water at −80° C.

Nomenclature

For consistency, the following nomenclature has been employed in theinstant specification. Names given to duplexes indicate the length ofthe oligomers and the presence or absence of overhangs. A “25/27” is anasymmetric duplex having a 25 base sense strand and a 27 base antisensestrand with a 2-base 3′-overhang. A “27/25” is an asymmetric duplexhaving a 27 base sense strand and a 25 base antisense strand.

Cell Culture and RNA Transfection

Huh7 cells were obtained and maintained in DMEM (HyClone) supplementedwith 10% fetal bovine serum (HyClone) at 37° C. under 5% CO₂. For RNAtransfections, cells were transfected with DsiRNAs at a finalconcentration of 1 nM, 0.1 nM or 0.03 nM using Lipofectamine™ RNAiMAX(Invitrogen) and following manufacturer's instructions. Briefly, for 0.1nM transfections, e.g., of Example 3 below, an aliquot of stock solutionof each DsiRNA was mixed with Opti-MEM I (Invitrogen) and Lipofectamine™RNAiMAX to reach a volume of 150 μL (with 0.3 nM DsiRNA). The resulting150 μL mix was incubated for 20 min at RT to allow DsiRNA:Lipofectamine™RNAiMAX complexes to form. Meanwhile, target cells were trypsinized andresuspended in medium. At the end of the 20 min of complexation, 50 uLof the DsiRNA:RNAiMAX mixture was added per well into triplicate wellsof 96 well plates. Finally, 100 μL of the cell suspension was added toeach well (final volume 150 μL) and plates were placed into theincubator for 24 hours.

Assessment of α-1 Antitrypsin Inhibition

α-1 antitrypsin target gene knockdown was determined by qRT-PCR, withvalues normalized to HPRT and SFRS9 housekeeping genes, and totransfections with control DsiRNAs and/or mock transfection controls.

RNA Isolation and Analysis

Media was aspirated, and total RNA was extracted using the SV96 kit(Promega). Total RNA was reverse-transcribed using SuperscriptII, OligodT, and random hexamers following manufacturer's instructions.Typically, the resulting cDNA was analyzed by qPCR using primers andprobes specific for both the α-1 antitrypsin gene and for the humangenes HPRT-1 and SFRS9. An ABI 7700 was used for the amplificationreactions. Each sample was tested in triplicate. Relative α-1antitrypsin RNA levels were normalized to HPRT1 and SFRS9 RNA levels andcompared with RNA levels obtained in transfection control samples.

Example 2: DsiRNA Inhibition of α-1 Antitrypsin

DsiRNA molecules targeting α-1 antitrypsin were designed and synthesizedas described above and tested in human Huh7 cells (alternatively, HepG2or other human cells could have been used) for inhibitory efficacy. Fortransfection, annealed DsiRNAs were mixed with the transfection reagent(Lipofectamine™ RNAiMAX, Invitrogen) and incubated for 20 minutes atroom temperature. The Huh7 (human) or AML12 (mouse) cells(alternatively, mouse Hepa 1-6 or other mouse cells could have beenused) were trypsinized, resuspended in media, and added to wells (100 uLper well) to give a final DsiRNA concentration of 1 nM in a volume of150 μl. Each DsiRNA transfection mixture was added to 3 wells fortriplicate DsiRNA treatments. Cells were incubated at 37° C. for 24hours in the continued presence of the DsiRNA transfection mixture. At24 hours, RNA was prepared from each well of treated cells. Thesupernatants with the transfection mixtures were first removed anddiscarded, then the cells were lysed and RNA was prepared from eachwell. Target α-1 antitrypsin RNA levels following treatment wereevaluated by qRT-PCR for the α-1 antitrypsin target gene, with valuesnormalized to those obtained for controls. Triplicate data was averagedand the % error was determined for each treatment. Normalized data wereboth tablulated and graphed, and the reduction of target mRNA by activeDsiRNAs in comparison to controls was determined (see Table 22 below andFIGS. 2A to 2D).

TABLE 22 α-1 Antitrypsin Inhibitory Efficacy of DsiRNAs Assayed at 1 nMin Human Huh7 and Mouse AML12 Cells Human - Huh7 Mouse - AML12Normalized HPRT/SFRS9 vs Normalized HPRT/Rpl23 vs NC1, NC5, NC7 NC1,NC5, NC7 Hs 462-563 Hs 1811-1910 Mm 331-462 Mm 1532-1462 (FAM) Assay(HEX) Assay (FAM) Assay (HEX) Assay Mm Rhesus % % % % Duplex NameLocation Location Remaining Remaining Remaining Remaining AAT-364 335AAT-366 337 AAT-367 338 11.5 ± 8.7 58.7 ± 22.9 AAT-368 339 6.9 ± 14.467.2 ± 28.6 AAT-369 340 5.3 ± 21.7 81.5 ± 25.7 AAT-370 341 38.2 ± 1570.3 ± 21.6 AAT-371 342 8.7 ± 3.2 82 ± 28.2 AAT-391 362 9.8 ± N/A 60.8 ±N/A AAT-392 363 AAT-393 364 AAT-394 365 12.3 ± 13.1 33.8 ± 29.8 AAT-395366 2.6 ± 3.3 23.6 ± 7.1 AAT-475 446 2.5 ± 10.2 18.8 ± 3.6 AAT-477 4486.7 ± 11.5 38.1 ± 13.1 AAT-480 451 7.2 ± 8.1 38.9 ± 14.2 AAT-481 45212.1 ± 6.1 40.7 ± 13.1 AAT-482 453 AAT-483 454 10.2 ± 18.9 26.5 ± 21.2AAT-484 455 7.2 ± 8.8 22.1 ± 7.7 AAT-485 456 6.6 ± 9.5 20.6 ± 19.8AAT-486 457 1.6 ± 3.3 18.5 ± 5.5 AAT-487 458 7.8 ± 2.3 33.1 ± 7.9AAT-488 459 24.5 ± 7.8 45 ± 12.8 AAT-489 460 27.4 ± 8.9 54.3 ± 6.1AAT-490 461 2.6 ± 27.3 30.7 ± 9.3 AAT-491 462 2.6 ± 15.9 25 ± 8.2AAT-492 463 3.5 ± 5 25.4 ± 6.5 AAT-493 464 6.6 ± 20.1 34.6 ± 3.8 AAT-494465 18.5 ± 5 42.2 ± 8.2 AAT-495 466 7.2 ± 5 31.3 ± 9.2 AAT-496 467 1.3 ±1.7 21.6 ± 5.1 AAT-497 468 7.3 ± 11.9 30.3 ± 10.9 AAT-498 469 42.4 ± 4.164.8 ± 6.7 AAT-499 470 40.2 ± 3 59 ± 3.6 AAT-500 471 7.9 ± 5.6 26.3 ±3.1 AAT-501 472 9.4 ± 3.5 31.8 ± 8.6 AAT-502 473 11.5 ± 10.4 28.5 ± 7.9AAT-503 474 21.5 ± 6.4 38.3 ± 11 AAT-504 475 13.3 ± 7.8 36.1 ± 8.4AAT-505 328 17.9 ± 6.6 42.3 ± 3.1 40.4 ± 2.7 43.3 ± 5.2 AAT-506 329 33.5± 3.3 54.9 ± 7.5 51.7 ± 7.9 55.8 ± 8.6 AAT-507 330 26.5 ± 3.5 48 ± 3.856.8 ± 2.1 59.2 ± 2.9 AAT-508 331 10 ± 5.5 35.3 ± 5.3 26 ± 7.5 30.2 ±5.5 AAT-509 332 75.6 ± 2.1 98.3 ± 6.2 75.3 ± 5.1 77.3 ± 4 AAT-510 48188.4 ± 2.1 105. ± 3.8 AAT-512 483 31.6 ± 1.2 62.6 ± 4 AAT-513 484 13.1 ±5.5 27.4 ± 2.4 AAT-515 486 27 ± 6.8 44.9 ± 5.6 AAT-516 487 43 ± 7 63.6 ±17.4 AAT-517 488 22.8 ± 4.9 38.6 ± 4.4 AAT-518 489 20.7 ± 1.4 37.2 ± 5.8AAT-519 490 9.5 ± 7.6 24 ± 2 AAT-520 491 43.9 ± 1.7 63.8 ± 10.1 AAT-521492 7.4 ± 12.8 52.9 ± 15.8 AAT-522 493 35.6 ± 4.9 77.6 ± 15.8 AAT-523494 48.6 ± 9.4 98.5 ± 17.4 AAT-524 495 54.9 ± 8.9 122.3 ± 12.2 AAT-525496 20.3 ± 28.7 53.4 ± 23.3 AAT-526 497 5.2 ± 27.3 58.2 ± 7.1 AAT-527498 24.4 ± 13.3 81.1 ± 9.9 AAT-528 499 26.2 ± 13 82.3 ± 6.1 AAT-529 50053.4 ± 12.9 91.7 ± 26.6 AAT-530 501 40.8 ± 14.3 77.3 ± 23.4 AAT-531 50222.3 ± 10.5 53 ± 7 AAT-532 503 11.4 ± 6 39.5 ± 18 AAT-535 506 50 ± 9.859.5 ± 18.1 AAT-540 511 10.6 ± 6.6 34 ± 15.5 AAT-541 512 57.2 ± 1.8 82 ±0.4 AAT-552 523 10.4 ± 15.3 51.4 ± 7.7 AAT-555 526 71.2 ± 8.8 96.6 ±15.2 AAT-556 527 3.6 ± 12.8 35 ± 11.1 AAT-557 528 4 ± 11.6 28.5 ± 8.7AAT-558 529 12.8 ± 8.2 26.9 ± 5.3 AAT-579 550 7.9 ± 6.4 32.8 ± 11AAT-580 551 28.1 ± 3.4 46.1 ± 5.4 AAT-581 552 3 ± 14.9 29 ± 13.4 AAT-582553 12.5 ± 16 47.8 ± 6.9 AAT-583 554 5.9 ± 14.5 22.2 ± 26.5 AAT-584 55512.9 ± 15 28.6 ± 21.8 AAT-585 556 31.9 ± 18.8 54.7 ± 23.3 AAT-586 5573.3 ± 26.3 28.8 ± 19.8 AAT-587 558 5.6 ± 24 24.9 ± 31.1 AAT-632 603 13.7± 30.4 35.9 ± 28.4 AAT-633 604 43.2 ± 7.1 66.4 ± 15.6 AAT-634 605 17.2 ±12.5 42.4 ± 7.5 AAT-637 608 84.6 ± 2.8 89.5 ± 7.6 AAT-638 609 16.8 ±10.4 24.1 ± 14.3 AAT-671 642 39.2 ± 8.7 53 ± 12.8 AAT-673 644 8 ± 5.122.2 ± 6.4 AAT-674 645 27.9 ± 1.4 39.5 ± 2.4 AAT-675 646 11.2 ± 5.9 24.4± 14.5 AAT-676 647 92.1 ± 3.2 116.5 ± 5.4 AAT-734 705 74.3 ± 4.5 94.5 ±3.5 AAT-735 706 8.4 ± 11.2 17.1 ± 21.3 AAT-736 707 5.1 ± 8.8 9.6 ± 12.1AAT-737 708 2.8 ± 12.5 12.9 ± 4.4 AAT-738 709 8.3 ± 4.9 21 ± 14 AAT-739710 75.3 ± 9.1 79.8 ± 15.3 AAT-740 711 4 ± 4.5 12.6 ± 7.2 AAT-767 7383.5 ± 9.2 18.9 ± 12.4 AAT-768 739 57.5 ± 8.4 79.3 ± 8.9 AAT-801 772 56.1± 5.3 64 ± 5.3 AAT-802 773 12.8 ± 8.2 31.5 ± 5.5 AAT-803 774 8.4 ± 22.129.2 ± 34.4 AAT-804 775 42.7 ± 17.7 72.7 ± 17.6 AAT-805 776 6.7 ± 2833.3 ± 26.4 AAT-806 777 13.5 ± 20.9 35.2 ± 11.3 AAT-807 778 5.8 ± 11.532.3 ± 5.8 AAT-808 779 33.6 ± 6.5 7.8 ± 11.4 AAT-809 780 30.7 ± 3.3 44.8± 5.8 AAT-810 781 2.5 ± 11.5 16.7 ± 7.5 AAT-811 782 10.4 ± 6.9 21.5 ±4.2 AAT-812 783 2.4 ± 8.3 11.5 ± 6 AAT-813 784 15.3 ± 5.3 31.1 ± 3.4AAT-850 821 28.1 ± 9.1 42.4 ± 7 AAT-851 822 26.4 ± 3.7 44.6 ± 7.2AAT-852 823 22.7 ± 4.3 52.9 ± 9.8 AAT-853 824 4.2 ± 2.9 13.3 ± 19.9AAT-854 825 27.8 ± 6.7 39.1 ± 14.2 AAT-855 826 6.9 ± 7.4 20.3 ± 17.6AAT-856 827 11.3 ± 4.9 20.4 ± 7.4 AAT-857 828 5.1 ± 4.1 17.9 ± 5.4AAT-858 829 8 ± 9.8 16.2 ± 20.5 AAT-859 830 5 ± 1.9 23 ± 9.3 AAT-860 83158.4 ± 4.4 78.7 ± 10.1 AAT-861 832 83.5 ± 7.1 98.7 ± 4.3 AAT-862 833 5.5± 30.4 22.3 ± 29.8 AAT-863 834 21.1 ± 15.3 39.2 ± 14.1 AAT-864 835 72.9± 4.5 107.3 ± 7 AAT-865 836 29.1 ± 17.1 52 ± 16 AAT-866 837 7.3 ± 15.325.3 ± 4.7 AAT-867 838 32.1 ± 11.2 52.8 ± 9 AAT-868 839 43.1 ± 29.3 78.2± 17.5 AAT-869 840 110 ± 2.3 16.1 ± 5.5 AAT-870 841 23.9 ± 8.7 35.4 ±8.5 AAT-871 842 73.3 ± 3.3 85.9 ± 2.6 AAT-872 843 13.4 ± 2.8 29.7 ± 5.9AAT-896 867 5 ± 14.6 20.3 ± 6.8 AAT-897 868 4.2 ± 18 18.3 ± 10.1 AAT-898869 1.5 ± 5.2 13.4 ± 5.1 AAT-899 870 3.8 ± 28.3 21.7 ± 15.8 AAT-900 8714.6 ± 4.9 11.6 ± 8.3 AAT-901 872 4.4 ± 4 14.8 ± 17.4 AAT-902 873 5.2 ±1.4 16.5 ± 0.9 AAT-903 874 18.3 ± 5.9 35.8 ± 9.1 AAT-904 875 20.7 ± 3.837.2 ± 2.4 AAT-905 876 4.8 ± 3.3 20.5 ± 5 AAT-906 877 3.3 ± 8.1 18.4 ±2.9 AAT-907 878 11 ± 19.1 36.3 ± 17.4 AAT-908 879 21.3 ± 19.7 41.2 ±16.7 AAT-909 880 7.5 ± 17.9 32.8 ± 9.1 AAT-910 881 5.7 ± 24.9 28.8 ±11.8 AAT-911 882 4.4 ± 30 28.3 ± 27.3 AAT-912 883 15.1 ± 13.2 36.7 ±15.3 AAT-913 884 11.6 ± 18.8 33.9 ± 11.3 AAT-914 885 26 ± 24 53.8 ± 14.1AAT-915 886 30.2 ± 6.8 62.1 ± 10.3 AAT-916 887 17.6 ± 11 35.3 ± 10.5AAT-917 888 10.4 ± 8.7 28.7 ± 12.6 AAT-918 889 36.6 ± 5.3 53.2 ± 2.8AAT-919 890 64.9 ± 1.7 88.7 ± 3.2 AAT-922 893 11.4 ± 5.9 26.5 ± 4.9AAT-924 895 42 ± 4.9 58.2 ± 1.7 AAT-926 897 102.4 ± 3.3 132 ± 6 AAT-927898 113 ± 1.6 143.8 ± 6.1 AAT-928 899 15.2 ± 37 27.8 ± 23.2 AAT-929 90021.5 ± 1.9 38 ± 3.7 AAT-930 901 49.6 ± 5 60.6 ± 2.3 AAT-931 902 50.3 ±6.9 82.5 ± 12.2 AAT-932 903 77.5 ± 10.1 98 ± 4.3 AAT-933 904 21.8 ± 7.541.2 ± 8.7 AAT-934 905 38.3 ± 3.7 55.3 ± 7.5 AAT-935 906 13 ± 12.7 32.6± 7.1 AAT-968 939 16 ± 14.4 33.2 ± 17.8 AAT-969 940 104.5 ± 5.3 141.3 ±4.4 AAT-970 941 10.9 ± 19.6 26.6 ± 13.8 AAT-971 942 10.2 ± 11.5 30.8 ±6.2 AAT-973 944 52.9 ± 12.8 78 ± 15.9 AAT-974 945 57.3 ± 8.1 80.5 ± 7.5AAT-976 947 71.4 ± 9.7 101 ± 9.8 AAT-1023 994 17.2 ± 8.5 44.3 ± 10.3AAT-1024 995 11.5 ± 6.9 26.6 ± 13 AAT-1025 996 10.2 ± 7.2 21.2 ± 9.5AAT-1026 997 76.8 ± 2.7 98.8 ± 3.2 AAT-1055 1026 7.6 ± 2.7 22.9 ± 6.8AAT-1059 882 93.5 ± 3.4 119.7 ± 8.9 110.7 ± 5 103.7 ± 3.5 AAT-1060 88325.3 ± 5.5 62.7 ± 5.2 70.8 ± 3.2 61.5 ± 6.9 AAT-1061 884 61.8 ± 2.1110.2 ± 5.2 98.4 ± 4.2 91.4 ± 2.2 AAT-1062 885 72.2 ± 4.6 90.1 ± 7.3 97± 4.3 95.9 ± 3 AAT-1063 886 24.7 ± 5.4 43.5 ± 7.5 62 ± 5.2 63.7 ± 3.1AAT-1064 887 55.5 ± 7 72.8 ± 4.2 87.6 ± 6.7 90.9 ± 7.1 AAT-1065 888 23.2± 5.2 48.1 ± 3 60.8 ± 2.1 67.4 ± 2.9 AAT-1066 1037 9.1 ± 3.2 24.6 ± 3AAT-1067 1038 12.8 ± 3.9 32 ± 7.5 AAT-1068 1039 47 ± 7.5 62.7 ± 6.9AAT-1069 1040 8.2 ± 9.1 28.5 ± 10.8 AAT-1070 1041 11 ± 4.6 20.8 ± 19.1AAT-1072 1043 65.1 ± 2.4 77.9 ± 5.5 AAT-1073 1044 15 ± 7.9 26.7 ± 3.8AAT-1074 1045 47.7 ± 1.1 71.1 ± 1.1 AAT-1075 1046 20.2 ± N/A 29.7 ± N/AAAT-1076 1047 82.6 ± 1.9 94.9 ± 2.1 AAT-1077 1048 11.9 ± 2.6 26 ± 7.8AAT-1078 1049 16.6 ± 3.6 42.5 ± 1.3 AAT-1079 1050 40.3 ± 13.8 74.4 ± 8.2AAT-1080 1051 21.9 ± 7.7 60 ± 12.9 AAT-1081 1052 43.5 ± 15.7 64.8 ± 13.4AAT-1083 1054 87.1 ± 9.3 124.7 ± 12.6 AAT-1095 1066 15.3 ± 16.2 44.6 ±23.1 AAT-1096 1067 5.1 ± 17.4 34.2 ± 27.5 AAT-1097 1068 53.1 ± 9.1 76.4± 17.7 AAT-1099 1070 99.1 ± 4.1 119.5 ± 11.4 AAT-1100 1071 74.9 ± 4.795.6 ± 6.9 AAT-1101 1072 39.8 ± 6.8 55.1 ± 13.9 AAT-1102 1073 18.5 ± 1.630.8 ± 4.8 AAT-1103 1074 35.9 ± 4.2 47.3 ± 3.7 AAT-1104 1075 8.3 ± 5.725.9 ± 11.5 AAT-1105 1076 9.5 ± 4.3 19.6 ± 9.1 AAT-1108 1079 7.6 ± 5.126.1 ± 2.7 AAT-1113 1084 91.1 ± 2.1 85.4 ± 7.8 AAT-1114 1085 56 ± 4.374.3 ± 4.8 AAT-1115 1086 13.1 ± 11.6 25.4 ± 21 AAT-1116 1087 5.8 ± 4.220.6 ± 13 AAT-1117 1088 15 ± 11.5 30 ± 18.1 AAT-1118 1089 6.6 ± 9.5 17.9± 10.8 AAT-1138 1109 36.3 ± 3.5 42 ± 5.4 AAT-1139 1110 127 ± 6.7 45.7 ±3.4 AAT-1140 1111 100.4 ± 6.2 105.5 ± 3.6 AAT-1141 1112 16.7 ± 32.6 47 ±34.4 AAT-1142 1113 18.9 ± 16.5 68.8 ± 12.2 AAT-1143 1114 10.1 ± 16 33.1± 21.4 AAT-1144 1115 19.7 ± 19.6 55.4 ± 31.2 AAT-1145 1116 31.4 ± 18.755.3 ± 26.9 AAT-1165 1136 41.6 ± 16.7 53.6 ± 15.3 AAT-1166 1137 12.5 ±15.7 45.6 ± 19 AAT-1167 1138 76.7 ± 4.5 92 ± 5.4 AAT-1168 1139 29.2 ± 653.4 ± 17.4 AAT-1169 1140 57.7 ± 5 75.2 ± 5 AAT-1170 1141 2.8 ± 8.7 26.3± 21.9 AAT-1171 1142 2.2 ± 6.8 30.1 ± 10.2 AAT-1172 1143 9.5 ± 6.4 23.2± 16.1 AAT-1173 1144 21 ± 5.1 36.4 ± 2.8 AAT-1174 1145 10.5 ± 1.5 38.3 ±10.5 AAT-1175 1146 9 ± 3.1 40.9 ± 1.4 AAT-1176 1147 16.4 ± 18.4 36 ±25.5 AAT-1232 1203 18.8 ± 11.6 36.5 ± 9.2 AAT-1233 1204 2.2 ± 6.4 15.4 ±5.5 AAT-1234 1205 3.8 ± 7 15.8 ± 7.1 AAT-1235 1206 3.7 ± 10.8 22.8 ±20.1 AAT-1236 1207 6.3 ± 2.3 21.1 ± 11.2 AAT-1237 1208 7.6 ± 12.7 30.3 ±31.2 AAT-1238 1209 52.8 ± 2.4 66.6 ± 9.6 AAT-1239 1210 9.1 ± 5.7 38.7 ±8.6 AAT-1240 1211 15 ± 13.9 41.8 ± 23.3 AAT-1279 1250 8.7 ± 24.8 32.1 ±24.3 AAT-1280 1251 11.3 ± 22.1 47.7 ± 19.8 AAT-1281 1252 56.5 ± 14.583.6 ± 15.6 AAT-1283 1254 69.8 ± 5.1 78.6 ± 7.8 AAT-1284 1255 89.3 ± 8116.1 ± 5.9 AAT-1286 1257 6.6 ± 1.8 46.4 ± 5.7 AAT-1296 1119 85.8 ± 5.4107.3 ± 5 77.8 ± 1.4 80.1 ± 3.4 AAT-1297 1120 85.6 ± 14.2 104.2 ± 11.694.4 ± 5.7 97.5 ± 3.5 AAT-1298 1121 94.6 ± 10.8 125.2 ± 7.3 80.7 ± 5.185 ± 6.5 AAT-1324 1295 49.8 ± 10 64.3 ± 13.8 AAT-1325 1296 38.5 ± 5.8 54± 10.6 AAT-1326 1297 6.7 ± 5.4 27.7 ± 9.4 AAT-1336 1307 19.5 ± 4.6 38.1± 15.1 AAT-1337 1308 34.1 ± 3.6 53.1 ± 3 AAT-1338 1309 78 ± 6.4 82.4 ±2.6 AAT-1339 1310 8.4 ± 5.3 37.6 ± 14.8 AAT-1348 1319 22.6 ± 4.9 49 ±5.3 AAT-1352 1323 19.9 ± 2.3 35.9 ± 15.2 AAT-1353 1324 3.4 ± 6.3 18.8 ±8 AAT-1354 1180 37.9 ± 5.6 65.9 ± 12.6 64.8 ± 3.3 68.4 ± 5.5 AAT-13551181 30.3 ± 6.8 51.4 ± 9.7 52.5 ± 10.6 65.7 ± 4 AAT-1356 1182 39.7 ± 2.655.8 ± 5.6 53.4 ± 2.1 58.4 ± 5.7 AAT-1357 1183 22.5 ± 5.4 36.6 ± 3.134.3 ± 8 41.9 ± 5.5 AAT-1358 1184 22.7 ± 8.1 41.2 ± 10.2 33.6 ± 2.4 41.9± 4.3 AAT-1359 1185 46.2 ± 4.9 59.5 ± 8.1 24.7 ± 16.2 27.5 ± 15.8AAT-1360 1186 7.7 ± 2.9 28.3 ± 8.3 19.9 ± 7.7 22.7 ± 4.6 AAT-1361 118711.1 ± 6 29 ± 1.2 14.5 ± 6 17.8 ± 9.9 AAT-1390 1361 55.2 ± 4.2 72.7 ± 9AAT-1391 1362 18.9 ± 5.7 44 ± 8.8 AAT-1392 1363 15.8 ± 2.4 31.8 ± 8.1AAT-1393 1364 66 ± 3.8 74.4 ± 2.7 AAT-1394 1365 54.5 ± 3.9 70.2 ± 7.5AAT-1395 1366 11.7 ± 5.9 50.8 ± 8.4 AAT-1404 1375 45.9 ± 11.7 71.1 ±12.5 AAT-1405 1376 47.3 ± 24.1 75.8 ± 30.3 AAT-1406 1377 11.6 ± 37 33.5± 21.1 AAT-1407 1378 24.1 ± 27.7 52.6 ± 26.2 AAT-1408 1379 10.4 ± 29.832.9 ± 25.7 AAT-1409 1380 56.7 ± 17.7 72.6 ± 20.1 AAT-1410 1381 75.9 ±8.6 107.5 ± 5.6 AAT-1411 1382 18.4 ± 6.2 58.8 ± 11.5 AAT-1412 1383 27.7± 23.1 44.4 ± 16.4 AAT-1413 1384 48.7 ± 3.8 66 ± 6.3 AAT-1414 1385 62.3± 9.1 72.2 ± 7.8 AAT-1415 1386 62.6 ± 5.1 82.8 ± 3.5 AAT-1416 1387 2.6 ±4.7 19.3 ± 2.7 AAT-1442 1413 5.6 ± 8.9 24.5 ± 8.6 AAT-1443 1414 3.4 ±13.6 25.6 ± 16.4 AAT-1444 1415 12.3 ± 7.4 40.7 ± 11.7 AAT-1445 1416 2.5± 6 20.5 ± 11.8 AAT-1446 1417 12.8 ± 9.3 19.6 ± 16.4 AAT-1447 1418 8.5 ±12 25.5 ± 13.5 AAT-1448 1419 2.4 ± 5.9 18.6 ± 14.5 AAT-1449 1420 2.2 ±4.6 15.9 ± 6.8 AAT-1450 1421 2.1 ± 8.5 17.2 ± 6 AAT-1451 1422 4.5 ± 5.823.3 ± 7 AAT-1452 1423 26.9 ± 2.1 56.7 ± 12.5 AAT-1453 1424 3.5 ± 2653.5 ± 29.2 AAT-1454 1425 4.7 ± 21.9 39.8 ± 22.4 AAT-1455 1426 7.7 ±38.9 39.7 ± 43.7 AAT-1456 1427 7.4 ± 22.9 41.7 ± 20.3 AAT-1457 1428 7.5± 27.6 47.5 ± 29.3 AAT-1458 1429 6.1 ± 20.3 53.2 ± 7.5 AAT-1459 1430 3.2± 10.6 41.1 ± 19.7 AAT-1460 1431 6.3 ± 14.8 40.8 ± 5.9 AAT-1461 1432 2.5± 12.5 32.9 ± 8.8 AAT-1462 1433 1.8 ± 4.4 23.4 ± 14.5 AAT-1463 1434 1.9± 4.7 23.8 ± 10.3 AAT-1464 1435 1.9 ± 6.8 19.5 ± 23 AAT-1465 1436 1.7 ±13.1 18.5 ± 14.5 AAT-1466 1437 9.3 ± 3.9 30.5 ± 3.5 AAT-1467 1438 56.6 ±2.2 70.4 ± 3.6 AAT-1468 1439 6.2 ± 3.7 44.2 ± 4.3 AAT-1469 1440 3.7 ±5.8 37.7 ± 8.2 AAT-1470 1441 3.2 ± 6.5 23.7 ± 4.2 AAT-1471 1442 1.6 ±13.5 18 ± 31.3 AAT-1472 1443 1.3 ± 12.3 17.8 ± 15.1 AAT-1473 1444 2.8 ±10.1 23.4 ± 10.2 AAT-1474 1445 4.5 ± 4.2 23.7 ± 4.2 AAT-1475 1446 11.1 ±7.4 45.6 ± 10.6 AAT-1476 1447 7.1 ± 4.8 38.8 ± 5.9 AAT-1477 1448 2.8 ±2.8 25.1 ± 9.6 AAT-1478 1449 5.2 ± 25.2 38.5 ± 24.7 AAT-1479 1450 13.3 ±23.3 27.8 ± 11.5 AAT-1480 1451 35.7 ± 22.6 62.7 ± 29.2 AAT-1481 1452 5.4± 18.5 32 ± 18.6 AAT-1482 1453 6.9 ± 22.6 24.8 ± 20.7 AAT-1483 1454 12.4± 10.4 44 ± 21.5 AAT-1484 1455 50.9 ± 4.9 59 ± 10.9 AAT-1485 1456 73.7 ±7.7 84.2 ± 2 AAT-1486 1457 13.7 ± 3.7 25.1 ± 8.4 AAT-1487 1458 11.7 ±9.5 20.9 ± 9.1 AAT-1488 1459 3.5 ± 8.4 13.8 ± 5.8 AAT-1489 1460 3.3 ± 515.1 ± 7.1 AAT-1490 1461 10.2 ± 3.6 25.5 ± 13.5 AAT-1491 1462 10 ± 5.723.2 ± 2.6 AAT-1492 1463 23.8 ± 4.8 42.2 ± 4 AAT-1493 1464 26.7 ± 4.544.3 ± 16.9 AAT-1494 1465 30.4 ± 3.7 37.1 ± 4.5 AAT-1495 1466 7.1 ± 4.219.4 ± 13.2 AAT-1496 1467 17.6 ± 4.7 29.6 ± 2.5 AAT-1497 1468 17.3 ± 5.121.6 ± 10.9 AAT-1499 1470 106.7 ± 10.4 81.1 ± 5 AAT-1501 1472 38 ± 2.138.7 ± 2.9 AAT-1502 1473 10.5 ± 5 26.5 ± 6.1 AAT-1503 1474 39.4 ± 7.152.6 ± 14.8 AAT-1504 1475 9.1 ± 6.3 26.6 ± 17.1 AAT-1505 1476 7.4 ± 1220.3 ± 9.8 AAT-1506 1477 60.9 ± 5.5 81.5 ± 2.5 AAT-1507 1478 3.9 ± 10.223.4 ± 10.9 AAT-1508 1479 5.4 ± 16.3 21.5 ± 22 AAT-1509 1480 12.7 ± 10.629.2 ± 25 AAT-1510 1481 5.7 ± 2.4 25.4 ± 27 AAT-1511 1482 15.7 ± 4.6 24± 8.5 AAT-1512 1483 57.5 ± 4.2 58.6 ± 7.8 AAT-1513 1484 6 ± 3.2 19.1 ±7.2 AAT-1514 1485 21.7 ± 7.2 28.8 ± 10.7 AAT-1515 1486 72.4 ± 1.1 71.8 ±0.6 AAT-1516 1487 18.3 ± 4.5 29.9 ± 8 AAT-1517 1488 6.6 ± 1 24.8 ± 2.4AAT-2872 122.6 ± 2.1 21.8 ± 15.2 AAT-2880 104.5 ± 7.5 20.2 ± 16.1AAT-3167 96.3 ± 2.3 20.8 ± 8.4 AAT-3169 90.4 ± 4.9 18.4 ± 5.9 AAT-317086.8 ± 8.8 25.7 ± 12.5 AAT-3172 93 ± 1.8 20.2 ± 3.2 AAT-3175 85.6 ± 1.615.1 ± 3.5 AAT-3180 90.2 ± 4.3 23.8 ± 5 AAT-3181 114.4 ± 4.1 28.7 ± 6.1AAT-3182 114.2 ± 0.8 31.1 ± 2.6 109.1 ± 7.2 102.4 ± 5.6

Example 3: DsiRNA Inhibition of α-1 Antitrypsin—Secondary Screen

96 asymmetric DsiRNAs (96 targeting Hs α-1 antitrypsin, 7 of which alsotargeted Mm α-1 antitrypsin) of the above experiment were then examinedin a secondary assay (“Phase 2”), with results of such assays presentedin histogram form in FIGS. 3A to 3H. Specifically, the 96 asymmetricDsiRNAs selected from those tested above were assessed for inhibition ofhuman α-1 antitrypsin at 1 nM, 0.1 nM and 0.03 nM in the environment ofhuman Huh7 cells (FIGS. 3A to 3D). These 96 asymmetric DsiRNAs were alsoassessed for inhibition of mouse α-1 antitrypsin at 1 nM, 0.1 nM and0.03 nM in the environment of mouse AML12 cells (FIGS. 3E to 3H). Asshown in FIGS. 3A to 3D, most asymmetric DsiRNAs reproducibly exhibitedsignificant human α-1 antitrypsin inhibitory efficacies at sub-nanomolarconcentrations when assayed in the environment of Huh7 cells. Inaddition, as shown in FIGS. 3E to 3H, a limited number of asymmetricDsiRNAs were identified to possess significant mouse α-1 antitrypsininhibitory efficacies at sub-nanomolar concentrations when assayed inthe environment of mouse AML12 cells.

Example 4: Modified Forms of α-1 Antitrypsin-Targeting DsiRNAs Reducedα-1 Antitrypsin Levels In Vitro

Twenty-four α-1 antitrypsin-targeting DsiRNAs of the above initialscreen (AAT-486, -490, -496, -508, -810, -898, -899, -911, -1069, -1360,-1361, -1449, -1450, -1453, -1458, -1459, -1460, -1461, -1462, -1463,-1465, -1471, -1476 and -1477) were prepared with 2′-O-methyl guide andpassenger strand modification patterns as shown in the schematics ofFIG. 4A (with individual strand modification patterns shown in isolationin FIG. 4B; modifications included “M107” modified passenger strands andabove-described guide strand modification patterns “M8”, “M17”, “M35”and “M48”). For each of the twenty-four DsiRNA sequences, DsiRNAspossessing each of the four guide strand modification patterns M8, M17,M35 and M48 were assayed for α-1 antitrypsin inhibition in human Huh7cells at 1.0 nM, 0.1 nM and 0.03 nM concentrations in the environment ofthe Huh7 cells. Results of these experiments are presented as histogramsin FIGS. 4C to 4F. In general, the twenty-four DsiRNA sequencesexhibited a trend towards reduced efficacy of α-1 antitrypsin inhibitionas the extent of 2′-O-methyl modification of the guide strand increased.However, for all DsiRNA sequences examined, a modification pattern couldbe identified that allowed the DsiRNA to retain significant α-1antitrypsin inhibitory efficacy in vitro. It was also notable that anumber of these DsiRNAs (e.g., AAT-486, AAT-490, AAT-899, AAT-911,AAT-1361, AAT-1458, AAT-1459, AAT-1460, AAT-1462, AAT-1463, AAT-1465 andAAT-1477) exhibited robust α-1 antitrypsin inhibitory efficacy in eventhe most highly modified states examined. Thus, such highly activemodified DsiRNA sequences possessed modification patterns believed to becapable of stabilizing such DsiRNAs and/or reducing immunogenicity ofsuch DsiRNAs when therapeutically administered to a subject in vivo.

Example 5: Additional Forms of α-1 Antitrypsin-Targeting DsiRNAsPossessing Modifications of Both Guide and Passenger Strands Reduced α-1Antitrypsin Levels In Vitro

Sixteen α-1 antitrypsin-Targeting DsiRNAs of the above experiments(AAT-490, AAT-496, AAT-810, AAT-898, AAT-899, AAT-1360, AAT-1361,AAT-1450, AAT-1453, AAT-1458, AAT-1459, AAT-1461, AAT-1462, AAT-1463,AAT-1471 and AAT-1477) were prepared with 2′-O-methyl passenger strandand guide strand modification patterns as represented above and in FIGS.5A to 5C (including passenger strand modification patterns “SM14”,“SM24”, “SM107”, “SM250”, “SM251” and “SM252” and guide strandmodification patterns “M48”, “M8” and “M17”). For each of the sixteenDsiRNA sequences, DsiRNAs possessing each of the six passenger strandmodification patterns M14, M24, M107, M250, M251 and M252 and onepreferred guide strand modification pattern (selected from among guidestrand modification patterns M48, M8 and M17) were assayed for α-1antitrypsin inhibition in human Huh7 cells at 1.0 nM, 0.1 nM and 0.03 nM(30 picomolar) concentrations in the environment of the Huh7 cells.Results of these experiments are presented as histograms in FIGS. 5D to5H. For all DsiRNA sequences examined, at least one duplex possessingextensive modification of both guide and passenger strands could beidentified that allowed the DsiRNA to retain significant α-1 antitrypsininhibitory efficacy in vitro. It was notable that many of these DsiRNAs(e.g., AAT-898, AAT-899, AAT-1461, AAT-1462, AAT-1463, AAT-1471 andAAT-1477) exhibited robust α-1 antitrypsin inhibitory efficacy acrossall modified states examined. Such highly active modified DsiRNAsequences possess modification patterns believed to be capable ofstabilizing such DsiRNAs and/or reducing immunogenicity of such DsiRNAswhen therapeutically administered to a subject in vivo.

Example 6: Synthesis and Testing of Single-Strand-Extended Forms of α-1Antitrypsin-Targeting dsRNAs

The following α-1 antitrypsin-targeting dsRNAs were also synthesized andpossessed single-stranded 5′ extensions of the guide strand (as alsoshown in FIG. 6A):

AAT-490-M250-ExM8 (SEQ ID NO: 2077) 5′-UCCAACAGCACCAAUAUCUUCUUct-3′(SEQ ID NO: 3493) 3′-UCAGGUUGUCGUGGUUAUAGAAGAAGAU

GCU

UCGT-5′ AAT-899-M252-ExM17 (SEQ ID NO: 73)5′-UUUUUGCUCUGGUGAAUUACAUCtt-3′ (SEQ ID NO: 3494)3′-UCAAAAACGAGACCACUUAAUGUAGAAU

GCU

UCGT-5′ AAT-1361-M250-ExM48 (SEQ ID NO: 134)5′-AGGCUGUGCUGACCAUCGACGAGaa-3′ (SEQ ID NO: 3495)3′-AUUCCGACACGACUGGUAGCUGCUCUUU

GCU

UCGT-5′ AAT-1462-M24-ExM17 (SEQ ID NO: 1787)5′-CCCUUUGUCUUCUUAAUGAUUGAac-3′ (SEQ ID NO: 3496)3′-UUGGGAAACAGAAGAAUUACUAACUUGU

GCU

UCGT-5′ AAT-1462-M252-ExM17 (SEQ ID NO: 1787)5′-CCCUUUGUCUUCUUAAUGAUUGAac-3′ (SEQ ID NO: 3496)3′-UUGGGAAACAGAAGAAUUACUAACUUGU

GCU

UCGT-5′ AAT-1463-M251-ExM48 (SEQ ID NO: 1788)5′-CCUUUGUCUUCUUAAUGAUUGAAca-3′ (SEQ ID NO: 3497)3′-UGGGAAACAGAAGAAUUACUAACUUGUU

GCU

UCGT-5′ AAT-1471-M250-ExM48 (SEQ ID NO: 1796)5′-UUCUUAAUGAUUGAACAAAAUACca-3′ (SEQ ID NO: 3498)3′-AGAAGAAUUACUAACUUGUUUUAUGGUU

GCU

UCGT-5′ AAT-1477-M251-ExM48 (SEQ ID NO: 1802)5′-AUGAUUGAACAAAAUACCAAGUCtc-3′ (SEQ ID NO: 3499)3′-AUUACUAACUUGUUUUAUGGUUCAGAGU

GCU

UCGT-5′where an underscore indicates a 2′-O-methyl RNA and “A” in bold, italicsindicates a 2′-Fluoro-adenine residue.

The above “single-strand-extended” (or “ss-extended”) forms of thedsRNAs of the invention were also tested for α-1 antitrypsin knockdownactivity in Huh7 cells, and as shown in FIG. 6B, all exhibited robustα-1 antitrypsin inhibitory efficacy, with all measured IC₅₀ values inthe 0.1 to 20 pM range, and the lowest measured IC₅₀ value of 0.1 pMobtained for the AAT-1477-M251-ExM48 extended dsNA (referred to as“SERPINA1 1477-M251-ExM48” in FIG. 6B). Each of these extended froms ofdsNA is also expected to exhibit a lack of immunogenicity (e.g.,effectively no induction of IFN and/or PKR effect(s)) when administeredin vivo and/or in an in vitro model or assay system for predicting orassessing in vivo immunogenicity, likely attributable to the maskingprovided by the modifications present within the single-strandextensions of these dsRNA sequences. Such dsRNA sequences possessmodification patterns believed to be capable of stabilizing such dsRNAsand/or reducing immunogenicity of such dsRNAs—even for dsRNAs of suchlength—when therapeutically administered to a subject in vivo.

Example 7: Assessment of In Vivo Efficacy of α-1 Antitrypsin-TargetingDsiRNAs

The ability of certain, active α-1 antitrypsin-targeting DsiRNAs toreduce α-1 antitrypsin levels within a mouse, optionally a mouse modelof liver disease is examined. Animals are randomized and assigned togroups based on marker levels. Dosing of animals with lipidnanoparticles (LNPs) containing DsiRNAs (optionally, an LNP formulationnamed EnCore-2072 is employed) is initiated on day 0. Animals are dosedat 5 mg/kg iv, tiw×2 (6 doses total). Animals are sacrificed 48 hrsafter the last dose. Liver is dissected and weighed, and α-1 antitrypsinlevels are assessed (optionally, for a mouse model of a liver disease ordisorder, the extent of reduction and/or prevention of the disease ordisorder is assessed).

Example 8: Indications

The present body of knowledge in α-1 antitrypsin research indicates theneed for methods to assay α-1 antitrypsin activity and for compoundsthat can regulate α-1 antitrypsin expression for research, diagnostic,and therapeutic use. As described herein, the nucleic acid molecules ofthe present invention can be used in assays to diagnose disease staterelated to α-1 antitrypsin levels. In addition, the nucleic acidmolecules can be used to treat disease state related to α-1 antitrypsinmisregulation, levels, etc.

Particular disorders and disease states that can be associated with α-1antitrypsin expression modulation include, but are not limited tochronic liver disease, liver inflammation, cirrhosis, liver fibrosis andhepatocellular carcinoma.

Other therapeutic agents can be combined with or used in conjunctionwith the nucleic acid molecules (e.g. DsiRNA molecules) of the instantinvention. Those skilled in the art will recognize that other compoundsand therapies used to treat the diseases and conditions described hereincan be combined with the nucleic acid molecules of the instant invention(e.g. siNA molecules) and are hence within the scope of the instantinvention. For example, for combination therapy, the nucleic acids ofthe invention can be prepared in one of at least two ways. First, theagents are physically combined in a preparation of nucleic acid andother agent, such as a mixture of a nucleic acid of the inventionencapsulated in liposomes and other agent in a solution for intravenousadministration, wherein both agents are present in a therapeuticallyeffective concentration (e.g., the other agent in solution to deliver1000-1250 mg/m2/day and liposome-associated nucleic acid of theinvention in the same solution to deliver 0.1-100 mg/kg/day).Alternatively, the agents are administered separately but simultaneouslyor successively in their respective effective doses (e.g., 1000-1250mg/m2/d other agent and 0.1 to 100 mg/kg/day nucleic acid of theinvention).

Example 9: Serum Stability for DsiRNAs

Serum stability of DsiRNA agents is assessed via incubation of DsiRNAagents in 50% fetal bovine serum for various periods of time (up to 24h) at 37° C. Serum is extracted and the nucleic acids are separated on a20% non-denaturing PAGE and can be visualized with Gelstar stain.Relative levels of protection from nuclease degradation are assessed forDsiRNAs (optionally with and without modifications).

Example 10: Diagnostic Uses

The DsiRNA molecules of the invention can be used in a variety ofdiagnostic applications, such as in the identification of moleculartargets (e.g., RNA) in a variety of applications, for example, inclinical, industrial, environmental, agricultural and/or researchsettings. Such diagnostic use of DsiRNA molecules involves utilizingreconstituted RNAi systems, for example, using cellular lysates orpartially purified cellular lysates. DsiRNA molecules of this inventioncan be used as diagnostic tools to examine genetic drift and mutationswithin diseased cells. The close relationship between DsiRNA activityand the structure of the target α-1 antitrypsin RNA allows the detectionof mutations in a region of the α-1 antitrypsin molecule, which altersthe base-pairing and three-dimensional structure of the target α-1antitrypsin RNA. By using multiple DsiRNA molecules described in thisinvention, one can map nucleotide changes, which are important to RNAstructure and function in vitro, as well as in cells and tissues.Cleavage of target α-1 antitrypsin RNAs with DsiRNA molecules can beused to inhibit gene expression and define the role of specified geneproducts in the progression of a α-1 antitrypsin-associated disease ordisorder. In this manner, other genetic targets can be defined asimportant mediators of the disease. These experiments will lead tobetter treatment of the disease progression by affording the possibilityof combination therapies (e.g., multiple DsiRNA molecules targeted todifferent genes, DsiRNA molecules coupled with known small moleculeinhibitors, or intermittent treatment with combinations of DsiRNAmolecules and/or other chemical or biological molecules). Other in vitrouses of DsiRNA molecules of this invention are well known in the art,and include detection of the presence of RNAs associated with a diseaseor related condition. Such RNA is detected by determining the presenceof a cleavage product after treatment with a DsiRNA using standardmethodologies, for example, fluorescence resonance emission transfer(FRET).

In a specific example, DsiRNA molecules that cleave only wild-type ormutant or polymorphic forms of the target α-1 antitrypsin RNA are usedfor the assay. The first DsiRNA molecules (i.e., those that cleave onlywild-type forms of target α-1 antitrypsin RNA) are used to identifywild-type α-1 antitrypsin RNA present in the sample and the secondDsiRNA molecules (i.e., those that cleave only mutant or polymorphicforms of target RNA) are used to identify mutant or polymorphic α-1antitrypsin RNA in the sample. As reaction controls, syntheticsubstrates of both wild-type and mutant or polymorphic α-1 antitrypsinRNA are cleaved by both DsiRNA molecules to demonstrate the relativeDsiRNA efficiencies in the reactions and the absence of cleavage of the“non-targeted” α-1 antitrypsin RNA species. The cleavage products fromthe synthetic substrates also serve to generate size markers for theanalysis of wild-type and mutant α-1 antitrypsin RNAs in the samplepopulation. Thus, each analysis requires two DsiRNA molecules, twosubstrates and one unknown sample, which is combined into six reactions.The presence of cleavage products is determined using an RNaseprotection assay so that full-length and cleavage fragments of each α-1antitrypsin RNA can be analyzed in one lane of a polyacrylamide gel. Itis not absolutely required to quantify the results to gain insight intothe expression of mutant or polymorphic α-1 antitrypsin RNAs andputative risk of α-1 antitrypsin-associated phenotypic changes in targetcells. The expression of α-1 antitrypsin mRNA whose protein product isimplicated in the development of the phenotype (i.e., diseaserelated/associated) is adequate to establish risk. If probes ofcomparable specific activity are used for both transcripts, then aqualitative comparison of α-1 antitrypsin RNA levels is adequate anddecreases the cost of the initial diagnosis. Higher mutant orpolymorphic form to wild-type ratios are correlated with higher riskwhether α-1 antitrypsin RNA levels are compared qualitatively orquantitatively.

All patents and publications mentioned in the specification areindicative of the levels of skill of those skilled in the art to whichthe invention pertains. All references cited in this disclosure areincorporated by reference to the same extent as if each reference hadbeen incorporated by reference in its entirety individually.

One skilled in the art would readily appreciate that the presentinvention is well adapted to carry out the objects and obtain the endsand advantages mentioned, as well as those inherent therein. The methodsand compositions described herein as presently representative ofpreferred embodiments are exemplary and are not intended as limitationson the scope of the invention. Changes therein and other uses will occurto those skilled in the art, which are encompassed within the spirit ofthe invention, are defined by the scope of the claims.

It will be readily apparent to one skilled in the art that varyingsubstitutions and modifications can be made to the invention disclosedherein without departing from the scope and spirit of the invention.Thus, such additional embodiments are within the scope of the presentinvention and the following claims. The present invention teaches oneskilled in the art to test various combinations and/or substitutions ofchemical modifications described herein toward generating nucleic acidconstructs with improved activity for mediating RNAi activity. Suchimproved activity can comprise improved stability, improvedbioavailability, and/or improved activation of cellular responsesmediating RNAi. Therefore, the specific embodiments described herein arenot limiting and one skilled in the art can readily appreciate thatspecific combinations of the modifications described herein can betested without undue experimentation toward identifying DsiRNA moleculeswith improved RNAi activity.

The invention illustratively described herein suitably can be practicedin the absence of any element or elements, limitation or limitationsthat are not specifically disclosed herein. Thus, for example, in eachinstance herein any of the terms “comprising”, “consisting essentiallyof”, and “consisting of” may be replaced with either of the other twoterms. The terms and expressions which have been employed are used asterms of description and not of limitation, and there is no intentionthat in the use of such terms and expressions of excluding anyequivalents of the features shown and described or portions thereof, butit is recognized that various modifications are possible within thescope of the invention claimed. Thus, it should be understood thatalthough the present invention has been specifically disclosed bypreferred embodiments, optional features, modification and variation ofthe concepts herein disclosed may be resorted to by those skilled in theart, and that such modifications and variations are considered to bewithin the scope of this invention as defined by the description and theappended claims.

In addition, where features or aspects of the invention are described interms of Markush groups or other grouping of alternatives, those skilledin the art will recognize that the invention is also thereby describedin terms of any individual member or subgroup of members of the Markushgroup or other group.

The use of the terms “a” and “an” and “the” and similar referents in thecontext of describing the invention (especially in the context of thefollowing claims) are to be construed to cover both the singular and theplural, unless otherwise indicated herein or clearly contradicted bycontext. The terms “comprising,” “having,” “including,” and “containing”are to be construed as open-ended terms (i.e., meaning “including, butnot limited to,”) unless otherwise noted. Recitation of ranges of valuesherein are merely intended to serve as a shorthand method of referringindividually to each separate value falling within the range, unlessotherwise indicated herein, and each separate value is incorporated intothe specification as if it were individually recited herein. All methodsdescribed herein can be performed in any suitable order unless otherwiseindicated herein or otherwise clearly contradicted by context. The useof any and all examples, or exemplary language (e.g., “such as”)provided herein, is intended merely to better illuminate the inventionand does not pose a limitation on the scope of the invention unlessotherwise claimed. No language in the specification should be construedas indicating any non-claimed element as essential to the practice ofthe invention.

Embodiments of this invention are described herein, including the bestmode known to the inventors for carrying out the invention. Variationsof those embodiments may become apparent to those of ordinary skill inthe art upon reading the foregoing description.

The inventors expect skilled artisans to employ such variations asappropriate, and the inventors intend for the invention to be practicedotherwise than as specifically described herein. Accordingly, thisinvention includes all modifications and equivalents of the subjectmatter recited in the claims appended hereto as permitted by applicablelaw. Moreover, any combination of the above-described elements in allpossible variations thereof is encompassed by the invention unlessotherwise indicated herein or otherwise clearly contradicted by context.Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such equivalents areintended to be encompassed by the following claims.

1-68. (canceled)
 69. A double stranded nucleic acid (dsNA) for reducing expression of α-1 antitrypsin mRNA comprising first and second nucleic acid strands that form a duplex region of 21 base pairs, wherein said first and second nucleic acid strands are separate nucleic acid molecules, wherein each of said first and second nucleic acid strands has a nucleotide sequence consisting of 21 nucleotides, wherein each of said 21 nucleotides of each of said first and second nucleic acid strands is a modified nucleotide, wherein said modified nucleotide is a 2′-O-methyl nucleotide or a 2′-fluoro nucleotide, wherein each of said first and second nucleic acid strands comprises one or more phosphorothioate linkages, wherein a targeting ligand is attached to said first nucleic acid strand, wherein said first nucleic acid strand comprises one or more inverted abasic residues, wherein the nucleotide sequence of the first nucleic acid strand consists of SEQ ID NO: 1908, and wherein said second strand is 100% complementary to SEQ ID NO:
 1908. 70. The dsNA of claim 69, wherein each of said first and second nucleic acid strands comprises a 3′-terminus, and wherein said first nucleic acid strand comprises the phosphorothioate linkage at said 3′-terminus or said second nucleic acid strand comprises the phosphorothioate linkage at said 3′-terminus or each of said first and second nucleic acid strands comprises the phosphorothioate linkage at said a 3′-terminus.
 71. The dsNA of claim 69, further comprising a targeting ligand attached to said second nucleic acid strand or both first and second nucleic acid strands.
 72. The dsNA of claim 69, wherein said targeting ligand comprises a GalNAc moiety or a tri-antennary GalNAc moiety.
 73. The dsNA of claim 69, wherein said first nucleic acid strand comprises two or more inverted abasic residues.
 74. The dsNA of claim 69, wherein said second nucleic acid strand comprises one or more inverted abasic residues.
 75. The dsNA of claim 73, wherein said targeting ligand comprises a GalNAc moiety or a tri-antennary GalNAc moiety.
 76. The dsNA of claim 69, wherein said first and second nucleic acid strands each comprise one or more modification patterns.
 77. The dsNA of claim 69, wherein said first nucleic strand comprises three or more phosphorothioate linkages
 78. The dsNA of claim 69, wherein said second nucleic strand comprises one or more phosphorothioate linkages.
 79. The dsNA of claim 78, wherein said second nucleic strand comprises three or more phosphorothioate linkages.
 80. A double stranded nucleic acid (dsNA) for reducing expression of α-1 antitrypsin mRNA comprising first and second nucleic acid strands that form a duplex region of 21 base pairs, wherein said first and second nucleic acid strands are separate nucleic acid molecules, wherein each of said first and second nucleic acid strands has a nucleotide sequence consisting of 21 nucleotides, wherein each of said 21 nucleotides of each of said first and second nucleic acid strands is a modified nucleotide, wherein said modified nucleotide is a 2′-O-methyl nucleotide or a 2′-fluoro nucleotide, wherein each of said first and second nucleic acid strands comprises three or more phosphorothioate linkages, wherein a targeting ligand is attached to said first nucleic acid strand, wherein said first nucleic acid strand comprises two or more inverted abasic residues, wherein the nucleotide sequence of the first nucleic acid strand consists of SEQ ID NO: 1908, and wherein said second strand is 100% complementary to SEQ ID NO:
 1908. 81. The dsNA of claim 80, wherein said targeting ligand comprises a GalNAc moiety or a tri-antennary GalNAc moiety.
 82. A pharmaceutical composition comprising the dsNA of claim 69 and a pharmaceutically acceptable carrier.
 83. A pharmaceutical composition comprising the dsNA of claim 80 and a pharmaceutically acceptable carrier.
 84. A method for reducing expression of a target α-1 antitrypsin mRNA in a human, the method comprising administering the dsNA of claim 69 to said human in an amount sufficient to reduce expression of said target α-1 antitrypsin mRNA in said human.
 85. A method for reducing expression of a target α-1 antitrypsin mRNA in a human, the method comprising administering the dsNA of claim 80 to said human in an amount sufficient to reduce expression of said target α-1 antitrypsin mRNA in said human. 